Endoplasmic Reticulum Stress in Nonalcoholic … Reticulum Stress in Nonalcoholic Fatty Liver...

NU32CH02-Pagliassotti ARI 9 July 2012 17:56

Endoplasmic ReticulumStress in Nonalcoholic FattyLiver DiseaseMichael J. PagliassottiDepartment of Food Science and Human Nutrition, Colorado State University,Fort Collins, Colorado 80523; email: [email protected]

Annu. Rev. Nutr. 2012. 32:17–33

The Annual Review of Nutrition is online atnutr.annualreviews.org

This article’s doi:10.1146/annurev-nutr-071811-150644

Copyright c© 2012 by Annual Reviews.All rights reserved

0199-9885/12/0821-0017$20.00

Keywords

unfolded protein response, obesity, hepatic steatosis, steatohepatitis,inflammation

Abstract

The underlying causes of nonalcoholic fatty liver disease are unclear,although recent evidence has implicated the endoplasmic reticulumin both the development of steatosis and progression to nonalcoholicsteatohepatitis. Disruption of endoplasmic reticulum homeostasis, oftentermed ER stress, has been observed in liver and adipose tissue of hu-mans with nonalcoholic fatty liver disease and/or obesity. Importantly,the signaling pathway activated by disruption of endoplasmic reticulumhomeostasis, the unfolded protein response, has been linked to lipidand membrane biosynthesis, insulin action, inflammation, and apopto-sis. Therefore, understanding the mechanisms that disrupt endoplasmicreticulum homeostasis in nonalcoholic fatty liver disease and the roleof the unfolded protein response in the broader context of chronic,metabolic diseases have become topics of intense investigation. Thepresent review examines the endoplasmic reticulum and the unfoldedprotein response in the context of nonalcoholic fatty liver disease.

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Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 18THE ENDOPLASMIC

RETICULUM AND THEUNFOLDED PROTEINRESPONSE. . . . . . . . . . . . . . . . . . . . . . . 18The Endoplasmic Reticulum . . . . . . . 18The Core UPR . . . . . . . . . . . . . . . . . . . . 19The Expanded UPR . . . . . . . . . . . . . . . 19

THE UPR AND THEDEVELOPMENT OFHEPATIC STEATOSIS. . . . . . . . . . . 20

THE UPR AND DISEASEPROGRESSION IN NAFLD. . . . . . 21JNK: A Common Link to Insulin

Action, Apoptosis, andInflammation . . . . . . . . . . . . . . . . . . . 21

Inflammation . . . . . . . . . . . . . . . . . . . . . . 22Oxidative Stress . . . . . . . . . . . . . . . . . . . . 23The ER and Cell Death . . . . . . . . . . . . 23Intestinal Function . . . . . . . . . . . . . . . . . 23Adipose Tissue . . . . . . . . . . . . . . . . . . . . 24Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 24

NUTRIENTS AND UPRACTIVATION. . . . . . . . . . . . . . . . . . . . 24

ACTIVATION OF THE UPR INHUMAN OBESITYAND NAFLD . . . . . . . . . . . . . . . . . . . . . 25

ER STRESS AND THE UPR INNAFLD: A CONCEPTUALFRAMEWORK . . . . . . . . . . . . . . . . . . . 25

CONCLUDING REMARKS . . . . . . . . . 26

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) iscurrently a global issue affecting both adultsand children (1, 89, 143). NAFLD is a dis-ease syndrome characterized by fatty infiltra-tion (steatosis) of the liver in the absence ofchronic alcohol consumption. In some indi-viduals, steatosis progresses to nonalcoholicsteatohepatitis (NASH), which is characterizedby steatosis, inflammation, apoptosis and fibro-sis, and end-stage liver disease (28).

The underlying causes of NAFLD are un-clear, although recent evidence has implicatedthe endoplasmic reticulum (ER) in both thedevelopment of steatosis and progression toNASH. Disruption of ER homeostasis, oftentermed ER stress, has been observed in liverand adipose tissue of humans with NAFLDand/or obesity (4, 19, 35, 96, 116). In addition,the signaling pathway activated by disruption ofER homeostasis, the unfolded protein response(UPR), has been linked to cellular perturbationsthat are common to obesity and NAFLD (55,68, 86). Therefore, understanding the mech-anisms that disrupt ER homeostasis and leadto activation of the UPR in chronic, metabolicdiseases have become topics of intenseinvestigation.

THE ENDOPLASMICRETICULUM AND THEUNFOLDED PROTEIN RESPONSE

The Endoplasmic Reticulum

The smooth ER produces structural phospho-lipids and cholesterol as well as significantamounts of triacylglycerol and cholesterol es-ters that have nonstructural roles (128). Thesmooth ER is the main site of cholesterol syn-thesis, although much of this lipid is transportedto other cellular organelles. The ER mem-brane is composed of very low concentrationsof cholesterol and complex sphingolipids (128).This loose packing of ER membrane lipids mayprovide an environment conducive to the inser-tion and transport of newly synthesized lipidsand proteins (128). The requirement for sucha specialized lipid environment may be rele-vant to diseases characterized by abnormal lipidaccumulation, such as NAFLD.

Proteins destined for secretion or inser-tion into membranes require modification, suchas glycosylation and disulfide bond formation,that cannot be achieved in the cytosol (71).The ER lumen provides a specialized environ-ment for protein folding and maturation and aunique complement of molecular chaperonesand folding enzymes (111). The presence of

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ER-associated degradation (ERAD) machineryhelps to ensure that improperly folded proteinsare retrotranslocated to the cytoplasm and tar-geted for proteasomal degradation. The UPRmonitors and responds to the accumulation ofimproperly folded proteins in the ER lumen(102).

The Core UPR

In mammalian cells, UPR activation involvesthree ER-localized proteins (Figure 1):inositol-requiring 1α (IRE1α), double-stranded RNA-dependent protein kinase-likeER kinase (PERK), and activating tran-scription factor-6α (ATF6α) (103). It iscurrently thought that in unstressed cells allthree proteins are maintained in an inac-tive state via their association with the ERprotein chaperone glucose-regulated protein78/immunoglobulin-heavy-chain-bindingprotein (GRP78). Upon ER stress, GRP78 isreleased and sequestered on unfolded proteins,allowing activation of PERK, IRE1α, andATF6 (149). PERK activation leads to phos-phorylation of the α-subunit of the translationinitiation factor eIF2 (p-eIF2α) and subsequentattenuation of translation initiation. Paradox-ically, p-eIF2α leads to selective translation ofmRNAs containing open reading frames, suchas activating transcription factor-4 (ATF4) (49,112). Increased expression of GADD34 (whichalso contains open reading frames), a memberof the growth arrest and DNA damage familyof proteins, is involved in dephosphorylationof eIF2α and therefore reversal of translationalattenuation (103). Activation of IRE1α pro-motes the splicing of X-box-binding protein-1(XBP1s) mRNA and subsequent transcriptionof molecular chaperones (e.g., GRP78) andgenes involved in ERAD [e.g., ER degradation-enhancing α—like protein (EDEM)] (112).IRE1α also appears to mediate rapid degrada-tion of specific mRNAs, presumably in an effortto reduce production of proteins that requirefolding in the ER lumen (40, 41). Activationof ATF6α leads to its release from the ERmembrane, processing in the Golgi, and entry

into the nucleus. Transcriptional targets ofATF6α include protein chaperones and XBP1(138). Thus, UPR activation initiates a coreresponse that includes transient attenuationof global protein synthesis and upregulationof protein folding and degradation. Thefundamental goal of this response is to removeunfolded proteins and restore ER homeostasis.

The Expanded UPR

PERK is one of four protein kinases thatcan phosphorylate eIF2α; the other three aredouble-stranded RNA-activated protein kinase(PKR), which is activated in response to viralinfection; general control nonderepressible2 kinase, which is activated in response toamino acid deprivation; and heme-regulatedinhibitor kinase, which is primarily expressedin reticulocytes and appears to coordinateglobin polypeptide synthesis with heme avail-ability (50). Protein kinase-mediated p-eIF2α

regulates not only translation but also theactivation of nuclear factor kappa-B (NFκB)via reduction in the abundance of the NFκBinhibitor IκB (88, 112, 139). PERK can alsophosphorylate nuclear erythroid 2 p45-relatedfactor 2 (Nrf2), triggering the nuclear importof Nrf2 (17). Thus, PERK-mediated p-eIF2α

links the UPR to inflammation, via NFκB andredox balance, via Nrf2.

IRE1α, in addition to catalyzing XBP1splicing, has functions related to cellular sig-naling. Activated IRE1α can interact withthe adaptor protein TNFR-associated factor2 (TRAF2) and lead to activation of c-Jun-NH2-terminal kinase ( JNK) and NFκB (127).IRE1α activation has also been linked to theactivation of p38 mitogen-activated protein ki-nase and extracellular-regulated kinase (39, 44,78). These interactions suggest that the IRE1α

branch of the UPR not only regulates adap-tation to ER stress and cell survival via XBP1splicing but also activation of signaling path-ways involved in inflammation, insulin action,and apoptosis.

ATF6α and XBP1s have been linked tolipid biosynthesis and ER membrane expansion

www.annualreviews.org • ER Stress and NAFLD 19

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via mechanisms that are partially distinct (6,121). Recent studies have also demonstratedthat the transcriptional activity of XBP1s canbe modified by acetylation/deacetylation andSUMOylation (13, 131). The ability to modifythe transcriptional activity of XBPs is a logicalmechanism to regulate the magnitude and/orselectivity of IRE1α-XBP1-mediated outputs.

Physical and functional links between theER and mitochondria have been demonstrated(8, 15). ER-mitochondrial coupling may pro-mote mitochondrial respiration and be influ-enced by ER stress and UPR activation (8).Chronic or severe ER stress may, in turn,modify cellular metabolism (132). Mitochon-drial energy metabolism may also support ERfunction (10). Mitochondrial function is closelyaligned with the development and/or exacerba-tion of chronic, metabolic diseases, includingNAFLD (69). It is likely that the alignment ofmitochondrial function with chronic, metabolicdiseases also involves the ER.

Much of what we know about ER stress andthe UPR has been derived from studies that uti-lize pharmacologic agents (tunicamycin, thap-sigargin). Much less is known about the UPR inthe context of physiologic stressors. In vivo, thediversity of ER stress-mediated UPR signalinglikely yields outcomes that are specific to thestress imposed and the needs of the involvedcell but may be broadly grouped into three po-tential outputs: adaptation (ER stress → UPRactivation → re-establishment of ER home-ostasis); alarm (ER stress → UPR activation →activation of signaling pathways involved in in-flammation, antioxidant defense, and/or insulinaction → re-establishment of ER homeostasisor mild, chronic ER stress); and apoptosis (ERstress → UPR activation → failure to resolvesevere ER stress → cell death) (52).

THE UPR AND THEDEVELOPMENT OFHEPATIC STEATOSIS

NAFLD is characterized by lipid accumula-tion in the liver in the absence of chronic al-cohol consumption or other liver disease (28).

Sources of hepatic lipids in NAFLD include di-etary chylomicron remnants, free fatty acids re-leased from adipose tissue triglycerides, and denovo lipogenesis (21, 22, 54). In addition, im-pairments in hepatic fatty acid oxidation and/orvery-low-density lipoprotein secretion mayalso contribute to hepatic lipid accumulation(34, 100).

XBP1 has been linked to hepatic lipogenesisand adipocyte differentiation (55, 115). Con-ditional disruption of Xbp1 in the liver led toreduced plasma levels of triglyceride, choles-terol, free fatty acids, and liver cell lipogene-sis in mice (55). Adipogenesis was also reducedin XBP1-deficient preadipocytes or MEF cells(115). The potential role of the IRE1α-XBP1pathway in the regulation of lipid biosynthesiswill likely depend on the physiologic setting.Recent studies have observed IRE1α-mediatedXBP1 splicing in the liver following a meal andin response to hyperinsulinemia (79, 93). In thiscontext, XBP1 may be an important determi-nant of lipid biosynthesis.

PERK and p-eIF2α also appear to regulatelipogenesis and hepatic steatosis. Targeteddeletion of PERK in mammary epitheliumreduced free fatty acids in milk, led to growthretardation in suckling pups, and reducedexpression of lipogenic genes (3). WhetherPERK-mediated regulation of lipogenesisoccurs in hepatocytes is presently unknown.GADD34 (PPP1R15a) encodes a regulatorysubunit of a phosphatase that selectivelydephosphorylates eIF2α. Enforced expressionof an active C-terminal fragment of GADD34in the liver reduced hepatic steatosis andexpression of the adipogenic nuclear receptorperoxisome proliferator-activated receptor-γ(PPARγ) and upstream regulators of PPARγ,CCAAT/enhancer-binding protein-α and -β(C/EBPα, C/EBPβ), in mice fed a high-fatdiet (83). Protein kinase–mediated p-eIF2α

increases the translation of a subset of genesthat include ATF4. The phenotype of ATF4heterozygous mice includes protection fromage-related and diet-induced obesity and diet-induced hepatic steatosis (114). Thus, whenthese studies are considered together it would

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appear that protein kinase–mediated p-eIF2α

can regulate the lipogenic transcriptionalprogram and perhaps the development ofhepatic steatosis.

ATF6α and sterol regulatory element–binding proteins (SREBPs) are ER-membrane-bound transcription factors that are activatedby proteolytic cleavage. At least one study hasdemonstrated that the nuclear form of ATF6α

inhibits the transcriptional activity of SREBP2by forming a complex with SREBP2 that re-cruits histone deacetylase-1 (147). The func-tional consequence of this interaction was to re-duce Oil-Red-O staining in liver cells. Thus, allthree proximal UPR sensors—PERK, IRE1α,and ATF6α—can regulate lipid stores in theliver. The degree to which the UPR contributesto hepatic steatosis may depend on the cel-lular event that elicits activation, the relativeresponse of the three proximal UPR sensors,and appropriate downstream protein-proteinand/or protein-DNA interactions.

A fundamental function of the UPR is torestore ER homeostasis in response to the ac-cumulation of unfolded proteins by reducingthe protein load entering the ER lumen and in-creasing the capacity of the ER to fold and de-grade proteins. The presence of ER stress andactivation of the UPR in chronic diseases suchas obesity and NAFLD implies that the abil-ity to resolve ER stress has been compromised.A recent study has examined the role of theUPR in hepatic steatosis from this perspective(104). Genetic ablation of eIF2α, IRE1α, orATF6α resulted in hepatic steatosis in responseto chemical induction of ER stress. Steatosis,in this model, appeared to result from impair-ments in the capacity to oxidize fatty acidsand was potentially augmented by impairedlipoprotein secretion. Thus, the UPR may pro-mote lipid homeostasis (i.e., prevent hepaticsteatosis) via its ability to maintain or rapidly re-establish ER homeostasis following ER stress.Perhaps development and/or exacerbation ofhepatic steatosis in the context of chronic dis-ease involve selective impairments to the UPRthat reduce the ability of the UPR to resolveER stress (104, 151).

Recent studies using GRP78 +/− mice andadenoviral-mediated overexpression of GRP78in vivo support this concept (48, 144). GRP78+/− mice were resistant to high-fat-diet-induced insulin resistance, hepatic steatosis,white adipose tissue inflammation, and hyper-glycemia (144). It was postulated that GRP78heterozygosity triggered an adaptive UPR,characterized by upregulation of other ERchaperones (e.g., GRP94) and components ofERAD machinery. The results of this study pre-dict that selective upregulation of protein chap-erones in the liver should improve insulin ac-tion and hepatic steatosis. Indeed, a recent studydemonstrated that selective overexpression ofGRP78 in the liver improved ER homeostasis,hepatic steatosis, and insulin action in ob/obmice (48).

THE UPR AND DISEASEPROGRESSION IN NAFLD

Liver pathology in NASH can includemacrovesicular steatosis, inflammation, fibro-sis, apoptosis, and necrosis (26, 87). Multiplefactors, including insulin resistance, oxidativestress, cytokine-mediated signaling, inflamma-tion, bacterial endotoxin, and excess fatty acidslikely function in concert to provoke diseaseprogression in NAFLD

JNK: A Common Link to InsulinAction, Apoptosis, and Inflammation

Obesity and insulin resistance are thought toplay an important role in the pathogenesis ofNAFLD (70, 87). ER stress may be linked toinsulin resistance via the ability of the UPRto regulate stress kinases, such as JNK andNFκB (11, 86). Activation of JNK can alsolead to liver damage and hepatocyte apopto-sis (18), the latter being a characteristic featureof NASH and correlated with disease severity(27, 135). Global deletion of JNK1, but notJNK2, reduced hepatic triglyceride accumula-tion, inflammation, liver injury, and apoptosisin methionine-choline-deficient diet–fed mice(109). In contrast, specific ablation of JNK1


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in hepatocytes produced a phenotype that in-cluded glucose intolerance, insulin resistance,and hepatic steatosis (105), suggesting that JNKisoforms may have tissue-specific actions thatdictate their roles in NAFLD.

Recent studies have also provided evidencethat XBP1 may be a central mediator of insulinaction and/or glucose homeostasis in the liver(56, 91, 137, 152). Haploinsufficiency of XBP1resulted in insulin resistance in mice (86), andthe ability of XBP1s to translocate to the nu-cleus was impaired in murine models of obe-sity (91). It also appears that XBP1s can interactwith phosphoinositide 3-kinase (PI3K) (91) andmay influence hepatic glucose metabolism in-dependently of insulin signaling, via interactionwith Foxo1 (152).

Inflammation

It is now well established that the NFκBpathway is an important determinant of theinflammatory response and insulin resistance(118). It is presently unclear whether and howUPR-mediated activation of NFκB is linkedto NAFLD. If the formation of the IRE1α-TRAF2 complex is crucial to activation of bothJNK and NFκB in NAFLD (44, 127), it willbe important to understand how and underwhat physiologic conditions these two pro-teins interact with the IRE1α-TRAF2 complex.Alternatively, it will be important to considerwhether ER stress-mediated activation of JNKand NFκB is shared among the three proximalUPR sensors, and if so, to identify the mech-anism by which this is accomplished. This lat-ter possibility may be particularly relevant giventhat NFκB can protect hepatocytes from oxida-tive stress and TNFα-induced cell death (32,61) as well as steatohepatitis and hepatocellularcarcinoma (64). Thus, the ultimate outcome ofNFκB activation likely depends on such factorsas the duration and magnitude of the stimulusand the interaction of NFκB with other signal-ing networks.

PKR is an interferon-induced serine/threonine protein kinase that is activated by

double-stranded RNA (23). PKR appears tobe required for NFκB activation in responseto double-stranded RNA, and therefore PKRhas been linked to immune and inflammatoryresponses (24). PKR activity is increased inadipose tissue and liver of murine models ofobesity and inhibits insulin signaling directlyand indirectly, the latter via activation ofJNK (76). The ability of PKR to respond topathogens, nutrients, and organelle stress andto regulate inflammatory and insulin-signalingpathways suggests that PKR may be a corecomponent of an inflammatory complex (43,76, 142). PKR can use catalysis-dependent and-independent activities to function both as apro- and antiapoptotic factor via regulation ofNFκB and p-eIF2α, respectively (24). Thus,it has been proposed that “PKR may serve as amolecular clock to time the sequential eventsof survival and death following virus infection”(24). It is feasible that other multifunctional,UPR-linked protein kinases employ similarstrategies to elicit cell- or stress-selectiveoutcomes.

Regulated intramembrane proteolysis(RIP), the release and transport of ER-residentproteins from the ER membrane to the Golgifor processing, may represent an importantlink between the ER and inflammation (75,99). ATF6α and SREBP both undergo RIPprior to their entry into the nucleus (149);thus, RIP is required for the activation ofone arm of the UPR and for transcriptionalregulation of the lipogenic program in theliver. CREBH, a transcription factor belongingto the CREB/ATF family of transcriptionfactors, is an RIP-regulated, liver-enrichedprotein that appears to be required for thehepatic synthesis of amyloid P-componentand C-reactive protein (63, 150). In addition,free fatty acids increase the expression ofCREBH, and proinflammatory cytokines andlipopolysaccharide induce the cleavage ofCREBH in the liver in vivo (33, 150). Thus,ER stress in the liver may be linked to systemicinflammation via RIP-mediated mobilizationof CREBH.

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Oxidative Stress

Protein folding in the ER is linked to the gen-eration of reaction oxygen species and oxidativestress (108, 117). Conversely, cellular oxida-tive stress can disrupt ER homeostasis (37, 140,145). Therefore, it is not surprising that theUPR can activate an antioxidant program viathe transcription factor Nrf2 (16). Nrf2 dele-tion results in rapid onset and progression ofsteatohepatitis in mice provided a methionine-choline-deficient diet (123). In addition, Nrf2-deficient mice were characterized by increasedmortality in response to endotoxin- and ce-cal ligation and puncture-induced septic shock(125). These studies have led to the proposalthat Nrf2 also participates in the regulation ofthe innate immune response. PERK-mediatedp-eIF2α also leads to the upregulation of ATF4.Along with Nrf2, ATF4 has been linked to themaintenance of cellular glutathione (17). Re-cent evidence has also linked the IRE1α-XBP1branch of the UPR to the regulation of an-tioxidant defenses (62). Thus, XBP1 may pro-vide protection from oxidative stress; however,whether this regulation occurs in hepatocytes ispresently unknown.

The ER and Cell Death

Hepatocyte apoptosis is increased in patientswith NASH and correlates with disease sever-ity; therefore, apoptosis has been proposed as acomponent of disease progression in NAFLD(27, 135). Failure of the UPR to ameliorateER stress can lead to cell death via severalmechanisms. C/EBP homologous protein(Chop) is among the best characterized of theUPR-regulated proapoptotic proteins (85).Chop expression is regulated by ATF4 andperhaps ATF6α, and deletion of Chop pro-vides some protection from ER stress–inducedcell death in both cells and animals (65, 81,85, 101, 120). Chop deficiency delayed thedevelopment of ER stress–mediated diabetes inAkita mice and attenuated cholestasis-inducedliver fibrosis (84, 124). However, the roleof Chop in NAFLD is unclear, as recent

evidence demonstrated that methionine-choline-deficient diet-induced liver injury wasnot reduced in Chop knockout mice (92).

It is possible that ER-mediated calciumrelease links the ER to alterations in mitochon-drial function and oxidative stress in NAFLD.For example, the release of ER calcium and sub-sequent calcium influx into mitochondria canlead to mitochondrial membrane permeabi-lization and activation of the intrinsic apoptoticpathway (20). A number of studies have demon-strated that ER stress, ER-localized proteins,and B-cell leukemia/lymphoma 2 protein (Bcl-2) protein family members interacting with ERlocalized proteins can regulate ER calcium flux(20, 57, 80, 113). Hepatic sarco-endoplasmicreticulum calcium-ATPase (SERCA) activityappears to be reduced in murine models ofobesity (29, 90), and modification of the ERmembrane lipid bilayer can also influence theactivity of SERCA (58). Thus, it is possible thatthe hepatic milieu in NAFLD modifies ERcalcium flux, perhaps via alterations in SERCA.

Autophagy is a cellular degradation processfor long-lived proteins and damaged organelles(53, 73, 74). Recent evidence has demonstratedthat inhibition of macroautophagy in culturedhepatocytes and mouse liver increased triglyc-eride storage in lipid droplets (119). ER stresscan trigger autophagy via mechanisms that mayrequire calcium-mediated activation of proteinkinase Cθ (107, 146). In addition, autophagy is anecessary pathway for the maintenance of struc-ture, mass, and function in pancreatic β-cells(47). One can envision that ER stress–mediatedactivation of autophagy may be part of the pro-tective, adaptive component of the UPR.

Intestinal Function

Bacterial translocation through the intestinalwall and small intestinal bacterial overgrowthmay be involved in the pathogenesis of NASH(136, 141). Recent studies have confirmed thepresence of increased plasma endotoxin and in-testinal permeability in humans with NAFLD(72, 126). Intestinal secretory cells may be sus-ceptible to ER stress because they produce large


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amounts of secretory proteins. It has been pro-posed that ER stress and UPR activation canlead to intestinal inflammation (25), which maybe an important component of disease progres-sion in NAFLD.

Adipose Tissue

Free fatty acids derived from adipose tissueare thought to play an important role in thedevelopment of hepatic steatosis (22). It isof interest, therefore, that a recent study inCaenorhabditis elegans suggested that IRE-1and HSP-4, the nematode IRE1 and GRP78homologs, respectively, regulate the expressionof the fasting-induced lipases, FIL-1 and -2(46). These lipases were both necessary andsufficient for fasting-induced fat granule hy-drolysis. In addition, free fatty acids can induceinflammation in adipose tissue via mechanismsthat involve PERK and IKKβ (45). Low levelsof adiponectin are linked to many features ofthe metabolic syndrome and liver fat accumula-tion (2, 94). Importantly, adipose tissue hypoxiahas been linked to ER stress and suppressionof adiponectin expression in adipose tissue(42). It is presently unclear whether the UPRcan regulate lipolysis in mammalian adiposetissue; however, given the evidence presentedabove, one can envision a role for this pathwayin adipose tissue lipolysis, inflammation, andadipokine release in the context of obesity andNAFLD.

Summary

ER-mediated signals are linked to a numberof downstream pathways that contribute to thepathogenesis of NAFLD. The extent to whichER stress and the UPR contribute to diseaseprogression in NAFLD will likely depend onthe ability of the UPR to alleviate the insultthat led to disruption of ER homeostasis. Thescenario most conducive to ER stress–mediateddisease progression likely involves chronic in-sults that provoke continuous ER stress coupled

to signals that reduce or impair the UPR’s abil-ity to alleviate those insults.

NUTRIENTS AND UPRACTIVATION

Several nutrient-related signals can activate theUPR. Elevated circulating free fatty acids are acharacteristic feature of NAFLD and are posi-tively correlated with liver disease severity (77).A growing body of evidence has demonstratedthat elevated free fatty acids—in particular,long-chain saturated fatty acids—induce ERstress and activation of the UPR in liver cells(5, 82, 134). Glycosylation is an essentialER luminal modification for proper stability,folding, translocation, and function of manyproteins (50). The hexosamine biosyntheticpathway plays a key role in glycosylation, andincreased flux through this pathway, whichcan occur under conditions of hyperglycemiaand/or hyperlipidemia, has been linked toPERK-dependent ER stress and attenuation ofApoB100 synthesis (97, 106). Oxidative stresshas also been linked to the development andprogression of a number of chronic diseasesincluding NAFLD (30, 129). Although theoxidation of cysteine residues during disulfidebond formation in the ER may be a significantsource of reactive oxygen species and leadto the development of oxidative stress (68),extraluminal sources of pro-oxidants can alsoinduce ER stress and promote the formationof inclusion bodies in liver cells (37, 67).

Apolipoprotein B100 (ApoB100) is animportant client protein in the liver. Thebiogenesis of ApoB100 requires co- andpost-translational modification, and studieshave identified interactions between newlysynthesized ApoB100 polypeptides and ERchaperone proteins, such as GRP78, GRP94,endoplasmic reticulum protein-72, calretic-ulin, and calnexin (14, 98, 148). Prolongedand/or severe ER stress can reduce ApoB100secretion; however, it has also been postulatedthat ApoB100 may serve as a molecular link

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between fatty acid–induced ER stress andinsulin resistance in hepatocytes (12, 82, 122).

ACTIVATION OF THE UPR INHUMAN OBESITY AND NAFLD

Activation of the UPR has been observed inliver and/or adipose tissue of dietary and ge-netic animal models of obesity, many of whichinclude features of NAFLD (5, 86, 130). Cur-rently only one study has compared markersof UPR activation in humans with or with-out NAFLD (96). In this study, liver sampleswere obtained from subjects with metabolicsyndrome and normal liver histology (controls,n = 17), subjects with metabolic syndromeand hepatic steatosis (NAFL, n = 21), andsubjects with metabolic syndrome and NASH(NASH, n = 21). Although livers from NAFLand NASH were characterized by increasedp-eIF2α, several other putative markers ofUPR activation were not increased (e.g., ATF4,Chop, GADD34, EDEM mRNA). Livers fromNASH subjects were additionally characterizedby a reduction in the amount of spliced XBP1mRNA.

Two studies have examined markers of UPRactivation in adipose tissue of obese, insulin-resistant subjects (4, 116). In one of thesestudies, subcutaneous fat biopsies were ob-tained from the upper thigh in lean [bodymass index (BMI) 24 ± 1.2 kg/m2, n = 6]and obese (BMI 33.5 ± 1.6 kg/m2, n = 6)healthy subjects (4). Adipose tissue from obesesubjects was characterized by increased pro-tein levels of calnexin, calreticulin, and pro-tein disulfide isomerase as well as increasedXBP1s mRNA and phosphorylation of JNK.In the second study, adipose tissue was ob-tained from 78 healthy, nondiabetic subjectsover a spectrum of BMIs (116). Several genemarkers associated with the UPR, includingGRP78, ATF6α, PERK, XBP1s, EDEM1, cal-reticulin, and oxygen-regulated protein 150,were significantly correlated to BMI. Correla-tions with BMI remained significant after con-trolling for contributions made by macrophagesusing CD68 gene expression.

One study examined both liver and adi-pose tissue in morbidly obese subjects (BMI51.3 ± 3 kg/m2, n = 11) prior to and oneyear following gastric bypass surgery (35). Sub-jects lost ∼40% of body weight at the one-yearfollow-up, at which time significant reductionswere observed in adipose tissue GRP78 mRNA,XBP1s mRNA, p-eIF2α, and phosphorylationof JNK. Liver samples were characterized byreduced staining for GRP78 and p-eIF2α.

A recent study analyzed hepatic gene net-works in morbidly obese patients with NAFLD(BMI 49.6 ± 7.4 kg/m2, n = 24, 89% female)or without NAFLD (BMI 48.8 ± 5.9, kg/m2,n = 25, 96% female) (31). Three genes associ-ated with the fibrosis pathway (COL1A1, IL10,and IGFBP3) were upregulated and one geneassociated with the UPR (HSPA5, also known asGRP78) was downregulated in patients withNAFLD compared with patients withoutNAFLD. Comprehensive analysis of the UPRis required in animal models of chronic diseaseand humans with obesity and NAFLD to betterdefine UPR activation/inactivation.

ER STRESS AND THE UPRIN NAFLD: A CONCEPTUALFRAMEWORK

ER stress is typically defined as the accumu-lation of mis- or unfolded proteins in theER lumen (50). Activation of the UPR inresponse to ER stress functions to removethese proteins and restore ER homeostasis.Based on this fundamental view, activation ofthe UPR or components of the UPR in obesityand NAFLD implies that mis- or unfoldedproteins have accumulated in the ER lumen ofthe liver and/or adipose tissue. This scenariopredicts that activation of the UPR in obesityand NAFLD results from an imbalance in theprotein load presented to the ER lumen andthe ability to fold, degrade, and/or transportthese proteins (Figure 2). Experimental sup-port for such a scenario includes studies thathave examined ER stress in pancreatic β-cells(110) and lipid-mediated ER stress in Chinesehamster ovary and liver cells (7, 133). It is also


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possible that physiologic signals that activatethe UPR in a regulatory or chronic fashionmay do so through mechanisms that operate inconcert with or distinct from the accumulationof unfolded proteins. For example, chronicdiseases such as obesity and NAFLD may alterthe composition of the ER membrane, which inturn may influence the function of any or all ofthe proximal UPR membrane-bound sensors(Figure 2). In fact, a recent study demonstratedthat membrane factors and unfolded proteinsactivate IRE1 via different mechanisms in yeast(95). Recent studies have also identified severalproteins that directly interact with and/orregulate the activity of IRE1 (36, 38, 60). In ad-dition, there appears to be a sensing mechanismwithin the lipid bilayer that triggers selectiveactivation of ATF6 (66). It is also possible thatcytosolic signals may interact with proximalUPR sensors and lead to selective activation ofcomponents of the UPR. Previous studies haveidentified links between growth factors and

PERK (59), and between PI3K signaling andPKR (51), that may be independent of unfoldedprotein accumulation. Moreover, the basalexpression of some ER chaperones appearsto be dependent on a mitogenic pathway thatis distinct from the ER stress–induced UPR(9).

CONCLUDING REMARKS

The UPR is a robust, highly efficient path-way that functions to remove unfolded proteinsfrom the ER lumen but also interacts with mul-tiple cellular-signaling pathways. The ability toresolve ER stress is closely linked to the mag-nitude and duration of the UPR. It is there-fore hypothesized that in the setting of chronicdiseases, the inability to mitigate signals thatinduce ER stress and/or activate the UPR cou-pled with signals that impair components of theUPR provide an environment that will promotedisease progression.

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

LITERATURE CITED

1. Argo CK, Caldwell SH. 2009. Epidemiology and natural history of non-alcoholic steatohepatitis.Clin. Liver Dis. 13:511–31

2. Berg AH, Combs TP, Scherer PE. 2002. ACRP30/adiponectin: an adipokine regulating glucose andlipid metabolism. Trends Endocrinol. Metab. 13:84–89

3. Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, et al. 2008. PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differ-entiation. Proc. Natl. Acad. Sci. USA 105:16314–19

4. Boden G, Duan X, Homko C, Molina EJ, Song W, et al. 2008. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 57:2438–44

5. Boden G, Song W, Duan X, Cheung P, Kresge K, et al. 2011. Infusion of glucose and lipids at physio-logical rates causes acute endoplasmic reticulum stress in rat liver. Obesity (Silver Spring) 19:1366–73

6. Bommiasamy H, Back SH, Fagone P, Lee K, Meshinchi S, et al. 2009. ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J. Cell Sci. 122:1626–36

7. Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE. 2006. Disruption of endoplasmicreticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 47:2726–37

8. Bravo R, Vicencio JM, Parra V, Troncoso R, Munoz JP, et al. 2011. Increased ER-mitochondrialcoupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J. CellSci. 124:2143–52

26 Pagliassotti

Ann

u. R

ev. N

utr.

201

2.32

:17-

33. D

ownl

oade

d fr

om w

ww

.ann

ualr

evie

ws.

org

by C

olor

ado

Stat

e U

nive

rsity

on

07/2

6/12

. For

per

sona

l use

onl

y.


9. Brewer JW, Cleveland JL, Hendershot LM. 1997. A pathway distinct from the mammalian unfoldedprotein response regulates expression of endoplasmic reticulum chaperones in non-stressed cells. EMBOJ. 16:7207–16

10. Burkart A, Shi X, Chouinard M, Corvera S. 2011. Adenylate kinase 2 links mitochondrial energymetabolism to the induction of the unfolded protein response. J. Biol. Chem. 286:4081–89

11. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, et al. 2005. Local and systemic insulin resistanceresulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11:183–90

12. Caviglia JM, Gayet C, Ota T, Hernandez-Ono A, Conlon DM, et al. 2011. Different fatty acids inhibitapoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy. J. LipidRes. 52:1636–51

13. Chen H, Qi L. 2010. SUMO modification regulates the transcriptional activity of XBP1. Biochem. J.429:95–102

14. Chen Y, Le Caherec F, Chuck SL. 1998. Calnexin and other factors that alter translocation affect therapid binding of ubiquitin to apoB in the Sec61 complex. J. Biol. Chem. 273:11887–94

15. Csordas G, Renken C, Varnai P, Walter L, Weaver D, et al. 2006. Structural and functional featuresand significance of the physical linkage between ER and mitochondria. J. Cell Biol. 174:915–21

16. Cullinan SB, Diehl JA. 2006. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 sig-naling pathway. Int. J. Biochem. Cell Biol. 38:317–32

17. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. 2003. Nrf2 is a direct PERKsubstrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23:7198–209

18. Czaja MJ. 2002. The future of GI and liver research: editorial perspectives. III. JNK/AP-1 regulation ofhepatocyte death. Am. J. Physiol. Gastrointest. Liver Physiol. 284:G875–79

19. Das SK, Chu WS, Mondal AK, Sharma NK, Kern PA, et al. 2008. Effect of pioglitazone treatment onendoplasmic reticulum stress response in human adipose and palmitate-induced stress in human liverand adipose cell lines. Am. J. Physiol. Endocrinol. Metab. 295:E393–400

20. Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, et al. 2008. Endoplasmic reticulum stressinduces calcium-dependent permeability transition, mitochondrial outer membrane permeabilizationand apoptosis. Oncogene 27:285–99

21. Diraison F, Moulin P, Beylot M. 2003. Contribution of hepatic de novo lipogenesis and reesterification ofplasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.Diabetes Metab. 29:478–85

22. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. 2005. Sources of fatty acidsstored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest.115:1343–51

23. Donze O, Abbas-Terki T, Picard D. 2001. The Hsp90 chaperone complex is both a facilitator and arepressor of the dsRNA-dependent kinase PKR. EMBO J. 20:3771–80

24. Donze O, Deng J, Curran J, Sladek R, Picard D, Sonenberg N. 2004. The protein kinase PKR: amolecular clock that sequentially activates survival and death programs. EMBO J. 23:564–71

25. Eri RD, Adams RJ, Tran TV, Tong H, Das I, et al. 2011. An intestinal epithelial defect conferring ERstress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol. 4:354–64

26. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. 2004. Natural history of nonalcoholic steato-hepatitis: a longitudinal study of repeat liver biopsies. Hepatology 40:820–26

27. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, et al. 2003. Hepatocyte apoptosis and fasexpression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–43

28. Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G. 2004. Hepatic steatosis in obese patients:clinical aspects and prognostic significance. Obes. Rev. 5:27–42

29. Fu S, Yang L, Li P, Hofmann O, Dicker L, et al. 2011. Aberrant lipid metabolism disrupts calciumhomeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528–31

30. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, et al. 2004. Increased oxidative stress inobesity and its impact on metabolic syndrome. J. Clin. Invest. 114:1752–61

31. Gawrieh S, Baye TM, Carless M, Wallace J, Komorowski R, et al. 2010. Hepatic gene networks inmorbidly obese patients with nonalcoholic fatty liver disease. Obes. Surg. 20:1698–709


Ann

u. R

ev. N

utr.

201

2.32

:17-

33. D

ownl

oade

d fr

om w

ww

.ann

ualr

evie

ws.

org

by C

olor

ado

Stat

e U

nive

rsity

on

07/2

6/12

. For

per

sona

l use

onl

y.


32. Geisler F, Algul H, Paxian S, Schmid RM. 2007. Genetic inactivation of RelA/p65 sensitizes adult mousehepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology 132:2489–503

33. Gentile CL, Wang D, Pfaffenbach KT, Cox R, Wei Y, Pagliassotti MJ. 2009. Fatty acids regulate CREBhvia transcriptional mechanisms that are dependent on proteasome activity and insulin. Mol. Cell Biochem.344:99–107

34. Ginsberg HN, Fisher EA. 2009. The ever-expanding role of degradation in the regulation of apolipopro-tein B metabolism. J. Lipid Res. 50(Suppl.):S162–66

35. Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, et al. 2009. Endoplasmic reticulum stressis reduced in tissues of obese subjects after weight loss. Diabetes 58:693–700

36. Gu F, Nguyen DT, Stuible M, Dube N, Tremblay ML, Chevet E. 2004. Protein-tyrosine phosphatase1B potentiates IRE1 signaling during endoplasmic reticulum stress. J. Biol. Chem. 279:49689–93

37. Hanada S, Harada M, Kumemura H, Omary MB, Koga H, et al. 2007. Oxidative stress induces theendoplasmic reticulum stress and facilitates inclusion formation in cultured cells. J. Hepatol. 47:93–102

38. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, et al. 2006. Proapoptotic BAX and BAK modulatethe unfolded protein response by a direct interaction with IRE1alpha. Science 312:572–76

39. Hetz C, Glimcher LH. 2009. Fine-tuning of the unfolded protein response: assembling the IRE1α

interactome. Mol. Cell 35:551–6140. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. 2009. Regulated Ire1-dependent decay of

messenger RNAs in mammalian cells. J. Cell Biol. 186:323–3141. Hollien J, Weissman JS. 2006. Decay of endoplasmic reticulum-localized mRNAs during the unfolded

protein response. Science 313:104–742. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, et al. 2007. Adipose tissue hypoxia in obesity

and its impact on adipocytokine dysregulation. Diabetes 56:901–1143. Hotamisligil GS. 2010. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.

Cell 140:900–1744. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. 2006. Autocrine tumor necrosis factor alpha links

endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediatedNF-kB activation and down-regulation of TRAF2 expression. Mol. Cell. Biol. 26:3071–84

45. Jiao P, Ma J, Feng B, Zhang H, Diehl JA, et al. 2011. FFA-induced adipocyte inflammation and insulinresistance: involvement of ER stress and IKKbeta pathways. Obesity (Silver Spring) 19:483–91

46. Jo H, Shim J, Lee JH, Lee J, Kim JB. 2009. IRE-1 and HSP-4 contribute to energy homeostasis viafasting-induced lipases in C. elegans. Cell Metab. 9:440–48

47. Jung HS, Chung KW, Won Kim J, Kim J, Komatsu M, et al. 2008. Loss of autophagy diminishespancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8:318–24

48. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, et al. 2009. GRP78 expression inhibitsinsulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest.119:1201–15

49. Kaufman RJ. 2002. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest.110:1389–98

50. Kaufman RJ. 1999. Stress signaling from the lumen of the endoplasmic reticulum: coordination of genetranscriptional and translational controls. Genes Dev. 13:1211–33

51. Kazemi S, Mounir Z, Baltzis D, Raven JF, Wang S, et al. 2007. A novel function of eIF2alpha kinases asinducers of the phosphoinositide-3 kinase signaling pathway. Mol. Biol. Cell 18:3635–44

52. Kim I, Xu W, Reed JC. 2008. Cell death and endoplasmic reticulum stress: disease relevance and thera-peutic opportunities. Nat. Rev. Drug Discov. 7:1013–30

53. Klionsky DJ. 2007. Autophagy: from phenomenology to molecular understanding in less than a decade.Nat. Rev. Mol. Cell Biol. 8:931–37

54. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. 2008. Liver, muscle, and adipose tissue insulin actionis directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134:1369–75

55. Lee A-H, Scapa EF, Cohen DE, Glimcher LH. 2008. Regulation of hepatic lipogenesis by the transcrip-tion factor XBP1. Science 320:1492–96

56. Lee J, Sun C, Zhou Y, Gokalp D, Herrema H, et al. 2011. p38 MAPK-mediated regulation of Xbp1s iscrucial for glucose homeostasis. Nat. Med. 17:1251–60

28 Pagliassotti

Ann

u. R

ev. N

utr.

201

2.32

:17-

33. D

ownl

oade

d fr

om w

ww

.ann

ualr

evie

ws.

org

by C

olor

ado

Stat

e U

nive

rsity

on

07/2

6/12

. For

per

sona

l use

onl

y.


57. Li G, Mongillo M, Chin KT, Harding H, Ron D, et al. 2009. Role of ERO1-alpha-mediated stimulationof inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J. CellBiol. 186:783–92

58. Li Y, Ge M, Ciani L, Kuriakose G, Westover EJ, et al. 2004. Enrichment of endoplasmic reticulum withcholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel withincreased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium storesand apoptosis in cholesterol-loaded macrophages. J. Biol. Chem. 279:37030–39

59. Li Y, Iida K, O’Neil J, Zhang P, Li S, et al. 2003. PERK eIF2alpha kinase regulates neonatal growth bycontrolling the expression of circulating insulin-like growth factor-I derived from the liver. Endocrinology144:3505–13

60. Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, et al. 2009. BAX inhibitor-1 is a negativeregulator of the ER stress sensor IRE1alpha. Mol. Cell 33:679–91

61. Liu H, Lo CR, Czaja MJ. 2002. NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosisthrough a sustained activation of JNK and c-Jun. Hepatology 35:772–78

62. Liu Y, Adachi M, Zhao S, Hareyama M, Koong AC, et al. 2009. Preventing oxidative stress: a new rolefor XBP1. Cell Death Differ. 16:847–57

63. Luebke-Wheeler J, Zhang K, Battle M, Si-Tayeb K, Garrison W, et al. 2008. Hepatocyte nuclear factor4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expres-sion of cyclic adenosine monophosphate responsive element binding protein H. Hepatology 48:1242–50

64. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, et al. 2007. Deletion of NEMO/IKKγ in liverparenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–32

65. Ma Y, Brewer JW, Diehl JA, Hendershot LM. 2002. Two distinct stress signaling pathways convergeupon the CHOP promoter during the mammalian unfolded protein response. J. Mol. Biol. 318:1351–65

66. Maiuolo J, Bulotta S, Verderio C, Benfante R, Borgese N. 2011. Selective activation of the transcriptionfactor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein. Proc. Natl.Acad. Sci. USA 108:7832–37

67. Malhotra JD, Kaufman RJ. 2007. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or adouble-edged sword? Antioxid. Redox Signal. 9:2277–93

68. Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, et al. 2008. Antioxidants reduce endoplasmicreticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA 105:18525–30

69. Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM. 2008. Mitochondrial dysfunction andoxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic. Biol.Med. 44:1259–72

70. Marchesini G, Brizi M, Morselli-Labate AM, Bianci G, Bugianesi E, et al. 1999. Association of nonal-coholic fatty liver disease with insulin resistance. Am. J. Med. 107:450–55

71. Marciniak S, Ron D. 2006. Endoplasmic reticulum stress signaling in disease. Physiol. Rev. 86:1133–4972. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, et al. 2009. Increased intestinal perme-

ability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49:1877–8773. Mizushima N. 2009. Physiological functions of autophagy. Curr. Top. Microbiol. Immunol. 335:71–8474. Mizushima N. 2005. The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell

Death Differ. 12(Suppl. 2):1535–4175. Mori K. 2003. Frame switch splicing and regulated intramembrane proteolysis: key words to understand

the unfolded protein response. Traffic 4:519–2876. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, et al. 2010. Double-stranded RNA-dependent

protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140:338–4877. Nehra V, Angulo P, Buchman AL, Lindor KD. 2001. Nutritional and metabolic considerations in the

etiology of nonalcoholic steatohepatitis. Dig. Dis. Sci. 46:2347–5278. Nguyen DT, Kebache S, Fazel A, Wong HN, Jenna S, et al. 2004. Nck-dependent activation of ex-

tracellular signal-regulated kinase-1 and regulation of cell survival during endoplasmic reticulum stress.Mol. Biol. Cell 15:4248–60

79. Ning J, Hong T, Ward A, Pi J, Liu Z, et al. 2011. Constitutive role for IRE1alpha-XBP1 signalingpathway in the insulin-mediated hepatic lipogenic program. Endocrinology 152:2247–55


Ann

u. R

ev. N

utr.

201

2.32

:17-

33. D

ownl

oade

d fr

om w

ww

.ann

ualr

evie

ws.

org

by C

olor

ado

Stat

e U

nive

rsity

on

07/2

6/12

. For

per

sona

l use

onl

y.


80. Oakes SA, Scorrano L, Opferman JT, Bassik MC, Nishino M, et al. 2005. Proapoptotic BAX and BAKregulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.Proc. Natl. Acad. Sci. USA 102:105–10

81. Okada T, Yoshida H, Akazawa R, Negishi M, Mori K. 2002. Distinct roles of activating transcriptionfactor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase(PERK) in transcription during the mammalian unfolded protein response. Biochem. J. 366:585–94

82. Ota T, Gayet C, Ginsberg HN. 2008. Inhibition of apolipoprotein B100 secretion by lipid-inducedhepatic endoplasmic reticulum stress in rodents. J. Clin. Invest. 118:316–22

83. Oyadomari S, Harding H, Zhang Y, Oyadomari M, Ron D. 2008. Dephosphorylation of translationinitiation factor 2αenhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7:520–32

84. Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, et al. 2002. Targeted disruption of the Chopgene delays endoplasmic reticulum-stress mediated diabetes. J. Clin. Invest. 109:525–32

85. Oyadomari S, Mori M. 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell DeathDiffer. 11:381–89

86. Ozcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, et al. 2004. Endoplasmic reticulum stress linksobesity, insulin action and type 2 diabetes. Science 306:457–61

87. Pagadala M, Zein CO, McCullough AJ. 2009. Predictors of steatohepatitis and advanced fibrosis innon-alcoholic fatty liver disease. Clin. Liver Dis. 13:591–606

88. Pahl HL, Baeuerle PA. 1995. A novel signal transduction pathway from the endoplasmic reticulum tothe nucleus is mediated by transcription factor NF-kappa B. EMBO J. 14:2580–88

89. Papandreou D, Rousso I, Mavromichalis I. 2007. Update on non-alcoholic fatty liver disease in children.Clin. Nutr. 26:409–15

90. Park SW, Zhou Y, Lee J, Lee J, Ozcan U. 2010. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is amajor regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc. Natl. Acad. Sci.USA 107:19320–25

91. Park SW, Zhou Y, Lee J, Lu A, Sun C, et al. 2010. The regulatory subunits of PI3K, p85alpha andp85beta, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 16:429–37

92. Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ. 2010. Linking endoplas-mic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemicalchaperones in palmitate-mediated cell death. Am. J. Physiol. Endocrinol. Metab. 298:E1026–35

93. Pfaffenbach KT, Nivala AM, Reese L, Ellis F, Wang D, et al. 2010. Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver. J. Nutr. 140:879–84

94. Pisto P, Ukkola O, Santaniemi M, Kesaniemi YA. 2011. Plasma adiponectin—an independent indicatorof liver fat accumulation. Metabolism 60:1515–20

95. Promlek T, Ishiwata-Kimata Y, Shido M, Sakuramoto M, Kohno K, Kimata Y. 2011. Membrane aber-rancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways.Mol. Biol. Cell 22:3520–32

96. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, et al. 2008. Activation and dysregulation of theunfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134:568–76

97. Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. 2009. Glucosamine-induced endoplasmic reticulum stressattenuates apolipoprotein B100 synthesis via PERK signaling. J. Lipid Res. 50:1814–23

98. Rashid KA, Hevi S, Chen Y, Le Caherec F, Chuck SL. 2002. A proteomic approach identifies proteinsin hepatocytes that bind nascent apolipoprotein B. J. Biol. Chem. 277:22010–17

99. Rawson RB. 2002. Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus.Essays Biochem. 38:155–68

100. Reddy JK, Rao MS. 2006. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acidoxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G852–58

101. Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, et al. 2006. Adaptation to ER stress is mediated bydifferential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 4:2024–41

102. Rutkowski DT, Hegde RS. 2010. Regulation of basal cellular physiology by the homeostatic unfoldedprotein response. J. Cell Biol. 189:783–94

30 Pagliassotti

Ann

u. R

ev. N

utr.

201

2.32

:17-

33. D

ownl

oade

d fr

om w

ww

.ann

ualr

evie

ws.

org

by C

olor

ado

Stat

e U

nive

rsity

on

07/2

6/12

. For

per

sona

l use

onl

y.


103. Rutkowski DT, Kaufman RJ. 2004. A trip to the ER: coping with stress. Trends Cell Biol. 14:20–28104. Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, et al. 2008. UPR pathways combine to

prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.Dev. Cell 15:829–40

105. Sabio G, Cavanagh-Kyros J, Ko HJ, Jung DY, Gray S, et al. 2009. Prevention of steatosis by hepaticJNK1. Cell Metab. 10:491–98

106. Sage AT, Walter LA, Shi Y, Khan MI, Kaneto H, et al. 2010. Hexosamine biosynthesis pathway fluxpromotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepaticcells. Am. J. Physiol. Endocrinol. Metab. 298:E499–511

107. Sakaki K, Kaufman RJ. 2008. Regulation of ER stress-induced macroautophagy by protein kinase C.Autophagy 4:841–43

108. Santos CX, Tanaka LY, Wosniak J, Laurindo FR. 2009. Mechanisms and implications of reactive oxygenspecies generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases,mitochondrial electron transport, and NADPH oxidase. Antioxid. Redox Signal. 11:2409–27

109. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, et al. 2006. JNK1 but not JNK2promotes the development of steatohepatitis in mice. Hepatology 43:163–72

110. Scheuner D, Kaufman RJ. 2008. The unfolded protein response: a pathway that links insulin demandwith beta-cell failure and diabetes. Endocr. Rev. 29:317–33

111. Schroder M, Kaufman RJ. 2005. ER stress and the unfolded protein response. Mutat. Res. 569:29–63112. Schroder M, Kaufman RJ. 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74:739–

89113. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, et al. 2003. BAX and BAK regulation

of endoplasmic reticulum calcium: a control point for apoptosis. Science 300:135–39114. Seo J, Fortuno ES, Suh JM, Stenesen D, Tang W, et al. 2009. ATF4 regulates obesity, glucose home-

ostasis, and energy expenditure. Diabetes 58:2565–73115. Sha H, He Y, Chen H, Wang C, Zenno A, et al. 2009. The IRE1α-XBP1 pathway of the unfolded

protein response is required for adipogenesis. Cell Metab. 9:556–64116. Sharma NK, Das SK, Mondal AK, Hackney OG, Chu WS, et al. 2008. Endoplasmic reticulum stress

markers are associated with obesity in nondiabetic subjects. J. Clin. Endocrinol. Metab. 93:4532–41117. Shimizu Y, Hendershot LM. 2009. Oxidative folding: cellular strategies for dealing with the resultant

equimolar production of reactive oxygen species. Antioxid. Redox Signal. 9:2317–31118. Shoelson SE. 2007. Obesity, inflammation, and insulin resistance. Gastroenterology 132:2169–80119. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, et al. 2009. Autophagy regulates lipid metabolism.

Nature 458:1131–35120. Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ. 2008. Chop deletion reduces oxidative stress,

improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin.Invest. 118:3378–89

121. Sriburi R, Jackowski S, Mori K, Brewer JW. 2004. XBP1: a link between the unfolded protein response,lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J. Cell Biol. 167:35–41

122. Su Q, Tsai J, Xu E, Qiu W, Bereczki E, et al. 2009. Apolipoprotein B100 acts as a molecular link betweenlipid-induced endoplasmic reticulum stress and hepatic insulin resistance. Hepatology 50:77–84

123. Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, et al. 2010. Deletion of nuclear factor-E2-relatedfactor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am. J. Physiol.Gastrointest. Liver Physiol. 298:G283–94

124. Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, et al. 2008. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am. J. Physiol. Gastrointest. Liver Physiol.294:G498–505

125. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, et al. 2006. Nrf2 is a critical regulatorof the innate immune response and survival during experimental sepsis. J. Clin. Invest. 116:984–95

126. Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, et al. 2008. Nonalcoholic fatty liver disease in hu-mans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrationsand with fructose intake. J. Nutr. 138:1452–55


Ann

u. R

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2.32

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ado

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on

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6/12

. For

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127. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, et al. 2000. Coupling of stress in the ER to activationof JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–66

128. van Meer G, Voelker DR, Feigenson GW. 2008. Membrane lipids: where they are and how they behave.Nat. Rev. Mol. Cell Biol. 9:112–24

129. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, et al. 2004. Oxidative stress-related parametersin the liver of non-alcoholic fatty liver disease patients. Clin. Sci. (Lond.) 106:261–68

130. Wang D, Wei Y, Pagliassotti MJ. 2006. Saturated fatty acids promote endoplasmic reticulum stress andliver injury in rats with hepatic steatosis. Endocrinology 147:943–51

131. Wang FM, Chen YJ, Ouyang HJ. 2010. Regulation of unfolded protein response modulator XBP1s byacetylation and deacetylation. Biochem. J. 433:245–52

132. Wang X, Eno CO, Altman BJ, Zhu Y, Zhao G, et al. 2011. ER stress modulates cellular metabolism.Biochem. J. 435:285–96

133. Wei Y, Wang D, Gentile CL, Pagliassotti MJ. 2009. Reduced endoplasmic reticulum luminal calciumlinks saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol. CellBiochem. 331:31–40

134. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. 2006. Saturated fatty acids induce endoplasmic retic-ulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. Endocrinol. Metab.291:E275–81

135. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. 2006. In vivo assessmentof liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology44:27–33

136. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. 2001. The role ofsmall intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factoralpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48:206–11

137. Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR. 2010. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded proteinresponse. Nat. Med. 16:438–45

138. Wu J, Kaufman RJ. 2006. From acute ER stress to physiological roles of the unfolded protein response.Cell Death Differ. 13:374–84

139. Wu S, Tan M, Hu Y, Wang JL, Scheuner D, Kaufman RJ. 2004. Ultraviolet light activates NFkappaBthrough translational inhibition of IkappaBalpha synthesis. J. Biol. Chem. 279:34898–902

140. Xue X, Piao JH, Nakajima A, Sakon-Komazawa S, Kojima Y, et al. 2005. Tumor necrosis factor alpha(TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependentfashion, and the UPR counteracts ROS accumulation by TNFalpha. J. Biol. Chem. 280:33917–25

141. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. 1997. Obesity increases sensitivity to endotoxinliver injury: implications for the pathogenesis of steatohepatitis. Proc. Natl. Acad. Sci. USA 94:2557–62

142. Yang X, Chan C. 2009. Repression of PKR mediates palmitate-induced apoptosis in HepG2 cells throughregulation of Bcl-2. Cell Res. 19:469–86

143. Yap JY, O’Connor C, Mager DR, Taylor G, Roberts EA. 2011. Diagnostic challenges of nonalcoholicfatty liver disease (NAFLD) in children of normal weight. Clin. Res. Hepatol. Gastroenterol. 35:500–5

144. Ye R, Jung DY, Jun JY, Li J, Luo S, et al. 2010. Grp78 heterozygosity promotes adaptive unfoldedprotein response and attenuates diet-induced obesity and insulin resistance. Diabetes 59:6–16

145. Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, et al. 2008. Involvement of selectivereactive oxygen species upstream of proapoptotic branches of unfolded protein response. J. Biol. Chem.283:4252–60

146. Yorimitsu T, Nair U, Yang Z, Klionsky DJ. 2006. Endoplasmic reticulum stress triggers autophagy.J. Biol. Chem. 281:30299–304

147. Zeng L, Lu M, Mori K, Luo S, Lee AS, et al. 2004. ATF6 modulates SREBP2-mediated lipogenesis.EMBO J. 23:950–58

148. Zhang J, Herscovitz H. 2003. Nascent lipidated apolipoprotein B is transported to the Golgi as anincompletely folded intermediate as probed by its association with network of endoplasmic reticulummolecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B. J. Biol. Chem. 278:7459–68

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149. Zhang K, Kaufman RJ. 2008. From endoplasmic reticulum stress to the inflammatory response. Nature454:455–62

150. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, et al. 2006. Endoplasmic reticulum stress activatescleavage of CREBH to induce a systemic inflammatory response. Cell 124:587–99

151. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, et al. 2011. The unfolded protein response trans-ducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J. 30:1357–75

152. Zhou Y, Lee J, Reno CM, Sun C, Park SW, et al. 2011. Regulation of glucose homeostasis through aXBP-1-FoxO1 interaction. Nat. Med. 17:356–65


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E RE RE R

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3 ER-localized proteins are inactive

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ER stress

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P

Figure 1Overview of the mammalian unfolded protein response. Accumulation of unfolded proteins provokes releaseof GRP78, activation of PERK, IRE1α, and ATF6, and subsequent attenuation of protein translation andactivation of gene transcription. Abbreviations: ATF6α, activating transcription factor-6α; ER, endoplasmicreticulum; ERAD, ER-associated degradation; GRP78, glucose-regulated protein78/immunoglobulin-heavy-chain-binding protein; IRE1α, inositol-requiring 1α; p-eIF2α, phosphorylationof the α-subunit of the translation initiation factor eIF2; PERK, protein kinase-like ER kinase; UPR,unfolded protein response.

www.annualreviews.org • ER Stress and NAFLD C-1

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Signal

Figure 2Hypothetical scenarios for unfolded protein response (UPR) activation. Unfolded proteins, membraneevents, and/or cytosolic signals may activate the UPR. Abbreviation: ER, endoplasmic reticulum.

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NU32-FrontMatter ARI 26 June 2012 13:26

Annual Review ofNutrition

Volume 32, 2012Contents

An Unexpected Life in NutritionMalden C. Nesheim � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver DiseaseMichael J. Pagliassotti � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �17

Modeling Metabolic Adaptations and Energy Regulation in HumansKevin D. Hall � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �35

Hypomagnesemia and Inflammation: Clinical and Basic AspectsWilliam B. Weglicki � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �55

Selenoproteins and Cancer PreventionCindy D. Davis, Petra A. Tsuji, and John A. Milner � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �73

The Role of Vitamin D in Pregnancy and Lactation:Insights from Animal Models and Clinical StudiesChristopher S. Kovacs � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �97

Vitamin A Metabolism in Rod and Cone Visual CyclesJohn C. Saari � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 125

Lipoprotein Lipase in the Brain and Nervous SystemHong Wang and Robert H. Eckel � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 147

New Roles of HDL in Inflammation and HematopoiesisXuewei Zhu and John S. Parks � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 161

Nutritional Metabolomics: Progress in Addressing Complexityin Diet and HealthDean P. Jones, Youngja Park, and Thomas R. Ziegler � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 183

Resolvins: Anti-Inflammatory and Proresolving Mediators Derivedfrom Omega-3 Polyunsaturated Fatty AcidsMichael J. Zhang and Matthew Spite � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 203

Visfatin/NAMPT: A Multifaceted Molecule with Diverse Rolesin Physiology and PathophysiologyTuva B. Dahl, Sverre Holm, Pal Aukrust, and Bente Halvorsen � � � � � � � � � � � � � � � � � � � � � � � 229

Gene-Environment Interactions in the Development of Type 2Diabetes: Recent Progress and Continuing ChallengesMarilyn C. Cornelis and Frank B. Hu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 245

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NU32-FrontMatter ARI 26 June 2012 13:26

Mechanisms of Inflammatory Responses in Obese Adipose TissueShengyi Sun, Yewei Ji, Sander Kersten, and Ling Qi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 261

Bone Metabolism in Obesity and Weight LossSue A. Shapses and Deeptha Sukumar � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 287

Obesity in Cancer SurvivalNiyati Parekh, Urmila Chandran, and Elisa V. Bandera � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 311

Inflammation in Alcoholic Liver DiseaseH. Joe Wang, Bin Gao, Samir Zakhari, and Laura E. Nagy � � � � � � � � � � � � � � � � � � � � � � � � � � � 343

Lessons Learned from Randomized Clinical Trials of MicronutrientSupplementation for Cancer PreventionSusan T. Mayne, Leah M. Ferrucci, and Brenda Cartmel � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 369

Population-Level Intervention Strategies and Examples for ObesityPrevention in ChildrenJennifer L. Foltz, Ashleigh L. May, Brook Belay, Allison J. Nihiser,

Carrie A. Dooyema, and Heidi M. Blanck � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 391

Type 2 Diabetes in Asians: Prevalence, Risk Factors, and Effectivenessof Behavioral Intervention at Individual and Population LevelsMary Beth Weber, Reena Oza-Frank, Lisa R. Staimez, Mohammed K. Ali,

and K.M. Venkat Narayan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 417

Indexes

Cumulative Index of Contributing Authors, Volumes 28–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � 441

Cumulative Index of Chapter Titles, Volumes 28–32 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 444

Errata

An online log of corrections to Annual Review of Nutrition articles may be found athttp://nutr.annualreviews.org/errata.shtml

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Endoplasmic Reticulum Stress in Nonalcoholic … Reticulum Stress in Nonalcoholic Fatty Liver...

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