Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances lipid...
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Abstracts / Chemistry and Physics of Lipids 164S (2011) S5–S8 S7 SO 7 Inhibition of class I histone deacetylases unveils a mitochon- drial signature and enhances lipid oxidation in skeletal muscle and adipose tissue Alessandra Ferrari 1,∗ , Andrea Galmozzi 1 , Nico Mitro 1 , Elise Gers 1 , Federica Gilardi 1 , Cristina Godio 3 , Gaia Cermenati 1 , Donatella Caruso 1 , Antonello Mai 2 , Enrique Saez 3 , Emma De Fabiani 1 , Maurizio Crestani 1 1 Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Milano, Italy 2 Dipartimento Studi Farmaceutici, Università degli Studi di Roma ‘La Sapienza’, Roma, Italy 3 Department of Chemical Physiology, The Scripps Research Institute, USA Many transcriptional and epigenetic mechanisms are involved in the regulation of lipid metabolism. Histone deacetylases and nuclear receptors play an important role in the regulation of lipid metabolism in adipose tissues, liver and skeletal muscles in normal and disease states. It has been shown that mitochondrial dysfunc- tion associated to unbalanced energy intake and expenditure could be a possible cause to the onset of obesity and insulin resistance. By using selective biochemical inhibitors here we show that class I histone deacetylases (HDACs) are important regulators of mito- chondrial lipid oxidation. MS275, a class I selective HDAC inhibitor, increased mitochondrial biogenesis and oxidative metabolism in C2C12 murine myotubes via upregulation of the transcriptional coactivator PGC-1a, a key determinant of mitochondrial biogenesis. Knock down of HDAC3 by RNAi increased the expression of PGC-1a and recapitulated the effects of MS275. Administration of MS275 to db/db mice improved the obese and diabetic phenotype, by reducing body weight, fasting glucose and insulin and by increas- ing insulin sensitivity. Metabolic studies showed elevated oxygen consumption in mice on MS275 and the concomitant decrease of the respiratory exchange ratio suggested a switch to lipid oxida- tive metabolism. In addition, higher heat production was noticed in mice treated with MS275, an effect paralleled by the improved functionality of brown adipose tissue consequent to increased expression of typical marker genes such as Ucp1, Prdm16, Adrb3, Pgc-1a. We also show that class I HDAC inhibitors cause a major reprogramming leading to a dramatic ‘browning’ of white adi- pose tissue (WAT) in a Prdm16-independent fashion and promote lipid catabolism and mitochondrial biogenesis. At the same time, infiltration of macrophages and the expression of inflammatory markers in WAT were reduced. In conclusion, biochemical inhibi- tion of class I HDACs revealed a mitochondrial signature mediated by the transcriptional coactivator Pgc-1a in skeletal muscle and by the Pgc-1a/Pparg axis in adipose tissue, leading to increased lipid oxidation and ultimately to insulin sensitizing effect in db/db mice. Acknowledgements: Funded by EU FP6 LSHM-CT2006-037498, Cariplo Foundation 2008.2511, The Armenise-Harvard Foundation and PRIN 2008 ZTN724. doi:10.1016/j.chemphyslip.2011.05.045 SO 8 Involvement of calcium-independent phospholipase A 2 in adi- pose differentiation Emiko Yoda, Shuntaro Hara ∗ Showa University, School of Pharmacy, Tokyo, Japan Adipose differentiation is a complex process by which fibroblast- like undifferentiated cells are converted into cells that accumulate lipid droplets. We here investigated the involvement of Ca 2+ - independent phospholipase A 2 (iPLA 2 ), a membrane-bound PLA 2 enzyme, in the regulation of adipose differentiation. We first found that gene deletion of iPLA 2 in mice reduced adipose tissue mass. Expressions of peroxisome proliferator activator (PPAR), a master regulator of adipose differentiation, and PPAR-regulated genes in adipose tissues of iPLA 2 knockout (KO) mice were also reduced as compared with wild-type (WT) mice. We next prepared mouse embryonic fibroblasts from WT and iPLA 2 KO mice and differentiated them into adipocytes. As the results, we found that iPLA 2 expression increased during adipose differentiation in WT mice-derived MEF, and that the differentiation was partially abol- ished in iPLA 2 KO mice-derived MEF. In KO mice-derived MEF, induction of PPAR and CAAT/enhancer-binding protein (C/EBP) was also reduced during adipogenesis, and the reduction in PPAR and C/EBP expression and the defect in adipose differentiation were restored by the treatment with troglitazone, a PPAR ligand. These results indicated that iPLA 2 is involved in adipose differen- tiation by regulating PPAR expression. doi:10.1016/j.chemphyslip.2011.05.046 SO 9 PPAR plays a key role in whole-body lipid homeostasis by reg- ulating transport and metabolism of unsaturated fatty acids in the liver Masahiro Terada, Kiyoto Motojima ∗ Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan On a standard diet, PPAR-null (KO) mice show little abnormali- ties in lipid metabolism although expression of some enzymes are significantly retarded. SCD1 was quite low in KO mouse liver. How- ever, compositions of major FAs in KO mouse liver were almost normal because of extra-hepatic compensation from the diet and/or adipose tissues where the expression level of SCD1 was main- tained. In detail, the levels of unsaturated (u) FAs were higher in KO mouse liver, and it was found in our present study that the increase was caused by decreased expression of a key peroxisomal enzyme in KO mouse liver and that the increased uFAs were the cause of repression of SCD1 through downregulaion of SREBP-1. RNAi knock-down of the key enzyme in wild type mouse liver repro- duced KO mice phenotype including downregulation of SCD1 and overexpression of the key enzyme in KO mouse liver reproduced wild type phenotype. Furthermore, overexpression of SREBP-1 in KO mice recovered the expression level of SCD1 in the liver. On a fat-free diet, KO mouse liver robustly induced FA synthesis enzymes including SCD1 and resultant excess hepatic lipogenesis produced fat accumulations in adipose tissues. In contrast to wild type mouse liver, KO mouse liver expressed low level of FATP1 which was essential for incorporation of essential uFAs from adipose tissues to suppress excess lipogenesis. Thus PPAR plays a key role in whole-body lipid homeostasis by maintaining uFA transport and catabolism in the liver. doi:10.1016/j.chemphyslip.2011.05.047
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Transcript of Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances lipid...
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whole-body lipid homeostasis by maintaining uFA transport andcatabolism in the liver.
doi:10.1016/j.chemphyslip.2011.05.047
Abstracts / Chemistry and Ph
O 7
nhibition of class I histone deacetylases unveils a mitochon-rial signature and enhances lipid oxidation in skeletal musclend adipose tissue
lessandra Ferrari 1,∗, Andrea Galmozzi 1, Nico Mitro 1, Elise Gers 1,ederica Gilardi 1, Cristina Godio 3, Gaia Cermenati 1, Donatellaaruso 1, Antonello Mai 2, Enrique Saez 3, Emma De Fabiani 1,aurizio Crestani 1
Dipartimento di Scienze Farmacologiche, Università degli Studi diilano, Milano, ItalyDipartimento Studi Farmaceutici, Università degli Studi di Roma ‘Laapienza’, Roma, ItalyDepartment of Chemical Physiology, The Scripps Research Institute,SA
any transcriptional and epigenetic mechanisms are involvedn the regulation of lipid metabolism. Histone deacetylases anduclear receptors play an important role in the regulation of lipidetabolism in adipose tissues, liver and skeletal muscles in normal
nd disease states. It has been shown that mitochondrial dysfunc-ion associated to unbalanced energy intake and expenditure coulde a possible cause to the onset of obesity and insulin resistance.y using selective biochemical inhibitors here we show that classhistone deacetylases (HDACs) are important regulators of mito-hondrial lipid oxidation. MS275, a class I selective HDAC inhibitor,ncreased mitochondrial biogenesis and oxidative metabolism in2C12 murine myotubes via upregulation of the transcriptionaloactivator PGC-1a, a key determinant of mitochondrial biogenesis.nock down of HDAC3 by RNAi increased the expression of PGC-1and recapitulated the effects of MS275. Administration of MS275o db/db mice improved the obese and diabetic phenotype, byeducing body weight, fasting glucose and insulin and by increas-ng insulin sensitivity. Metabolic studies showed elevated oxygenonsumption in mice on MS275 and the concomitant decrease ofhe respiratory exchange ratio suggested a switch to lipid oxida-ive metabolism. In addition, higher heat production was noticedn mice treated with MS275, an effect paralleled by the improvedunctionality of brown adipose tissue consequent to increasedxpression of typical marker genes such as Ucp1, Prdm16, Adrb3,gc-1a. We also show that class I HDAC inhibitors cause a majoreprogramming leading to a dramatic ‘browning’ of white adi-ose tissue (WAT) in a Prdm16-independent fashion and promote
ipid catabolism and mitochondrial biogenesis. At the same time,nfiltration of macrophages and the expression of inflammatory
arkers in WAT were reduced. In conclusion, biochemical inhibi-ion of class I HDACs revealed a mitochondrial signature mediatedy the transcriptional coactivator Pgc-1a in skeletal muscle and byhe Pgc-1a/Pparg axis in adipose tissue, leading to increased lipidxidation and ultimately to insulin sensitizing effect in db/db mice.
Acknowledgements: Funded by EU FP6 LSHM-CT2006-037498,ariplo Foundation 2008.2511, The Armenise-Harvard Foundationnd PRIN 2008 ZTN724.
oi:10.1016/j.chemphyslip.2011.05.045
O 8
nvolvement of calcium-independent phospholipase A2� in adi-ose differentiation
miko Yoda, Shuntaro Hara ∗
Showa University, School of Pharmacy, Tokyo, Japan
dipose differentiation is a complex process by which fibroblast-ike undifferentiated cells are converted into cells that accumulate
of Lipids 164S (2011) S5–S8 S7
lipid droplets. We here investigated the involvement of Ca2+-independent phospholipase A2� (iPLA2�), a membrane-boundPLA2 enzyme, in the regulation of adipose differentiation. We firstfound that gene deletion of iPLA2� in mice reduced adipose tissuemass. Expressions of peroxisome proliferator activator � (PPAR�),a master regulator of adipose differentiation, and PPAR�-regulatedgenes in adipose tissues of iPLA2� knockout (KO) mice were alsoreduced as compared with wild-type (WT) mice. We next preparedmouse embryonic fibroblasts from WT and iPLA2� KO mice anddifferentiated them into adipocytes. As the results, we found thatiPLA2� expression increased during adipose differentiation in WTmice-derived MEF, and that the differentiation was partially abol-ished in iPLA2� KO mice-derived MEF. In KO mice-derived MEF,induction of PPAR� and CAAT/enhancer-binding protein (C/EBP) �was also reduced during adipogenesis, and the reduction in PPAR�and C/EBP� expression and the defect in adipose differentiationwere restored by the treatment with troglitazone, a PPAR� ligand.These results indicated that iPLA2� is involved in adipose differen-tiation by regulating PPAR� expression.
doi:10.1016/j.chemphyslip.2011.05.046
SO 9
PPAR� plays a key role in whole-body lipid homeostasis by reg-ulating transport and metabolism of unsaturated fatty acids inthe liver
Masahiro Terada, Kiyoto Motojima ∗
Department of Biochemistry, Meiji Pharmaceutical University, Kiyose,Tokyo, Japan
On a standard diet, PPAR�-null (KO) mice show little abnormali-ties in lipid metabolism although expression of some enzymes aresignificantly retarded. SCD1 was quite low in KO mouse liver. How-ever, compositions of major FAs in KO mouse liver were almostnormal because of extra-hepatic compensation from the diet and/oradipose tissues where the expression level of SCD1 was main-tained. In detail, the levels of unsaturated (u) FAs were higher in KOmouse liver, and it was found in our present study that the increasewas caused by decreased expression of a key peroxisomal enzymein KO mouse liver and that the increased uFAs were the causeof repression of SCD1 through downregulaion of SREBP-1. RNAiknock-down of the key enzyme in wild type mouse liver repro-duced KO mice phenotype including downregulation of SCD1 andoverexpression of the key enzyme in KO mouse liver reproducedwild type phenotype. Furthermore, overexpression of SREBP-1 inKO mice recovered the expression level of SCD1 in the liver. On afat-free diet, KO mouse liver robustly induced FA synthesis enzymesincluding SCD1 and resultant excess hepatic lipogenesis producedfat accumulations in adipose tissues. In contrast to wild type mouseliver, KO mouse liver expressed low level of FATP1 which wasessential for incorporation of essential uFAs from adipose tissuesto suppress excess lipogenesis. Thus PPAR� plays a key role in
