aging.pharm.pusan.ac.krTranslate this pageaging.pharm.pusan.ac.kr/lab/lecture/2011_2/L7 Chap...
Transcript of aging.pharm.pusan.ac.krTranslate this pageaging.pharm.pusan.ac.kr/lab/lecture/2011_2/L7 Chap...
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Nucleotide metabolism 대사의 주요 개념도
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LEHNINGER PRINCIPLES OF BIOCHEMISTRY
Fifth Edition
David L. Nelson and Michael M. Cox
© 2008 W. H. Freeman and Company
CHAPTER 23 Hormonal Regulation and Integration of
Mammalian Metabolism
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생명현상의 Overview : 생명현상의 분자기전 Information
생체정보 : hormone, cytokines, neurotransmitter→세포→유전
O2/영양분 cytokines neurotransmitters Hormones 1st messenger
당질 (당뇨병)
지질→저장 (비만, 동맥경화)
-omics
°Physiome
⋅Genome=gene+chromosome -sequencing -SNP DNA chip ⋅Transcriptome ⋅Proteome -2D/Mass
Hormesis
Maintenance
E小
Cell proliferation (replication)
E多
2nd messenger
⋅Southern blot ⋅ Northern blot
⋅ Western blot
단백질
열
Protein (생리기능)
Cell homeostasis
themogenin ATP
Vt C, E
a.a
mRNA Vt B AAA
TCA
NADH
Signaling
Transcriptome Epigenome
Proteome
Metabolome Lipidome
Gerontome
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Signaling by the neuroendocrine system
E 대사기관
Epi, Ach
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Radioimmunoassay (RIA)
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Radioimmunoassay (RIA)
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Two general mechanisms of hormone action
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Insulin
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Proteolytic processing of the pro-opiomelanocortin (POMC) precursor
식욕억제
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NO
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The major endocrine glands
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The major endocrine systems and their target tissues
ng
ug
mg
CRH
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Neuroendocrine origins of hormone signals
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Neuroendocrine origins of hormone signals
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Two hormones of the posterior pituitary gland
ADH
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Cascade of hormone release following central nervous system input to the hypothalamus
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Specialized metabolic functions of mammalian tissues
대사중심
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Pathways of Carbohydrate, Amino Acid, and Fat Metabolism Illustrated in Earlier Chapters
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Metabolic pathways for glucose 6-phosphate in the liver
Glucokinase Hexokinase
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Metabolism of amino acids in the liver
식간 glu level 조절
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Metabolism of fatty acids in the liver
-albumin
공복시심장(1/3), 뇌(2/3) E원
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Adipocytes of white and brown adipose tissue
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FIGURE 17-3 Mobilization of triacylglycerols stored in adipose tissue.
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Distribution of brown adipose tissue in a newborn infant
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Energy sources for muscle contraction
Slow-twitch muscle: Mt, 혈관 많음,적색근, ATP생성 지속적 Fast-twitch muscle: Mt, 혈관 적음, 백색근, ATP 사용 빠름
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Metabolic cooperation between skeletal muscle and the liver: the Cori cycle
Glu- Ala cycle과 협력
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Electron micrograph of heart muscle
심장: 1분에 6L혈액 분출, Mt 많음, Cr-p, 동맥경화,혈전 FFA, Glu, Ketone body E원
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The fuels that supply ATP in the brain
막전위유지
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Glucose metabolism in the brain
휴식시
불면시
Glu만 사용, 20%산소사용 Ketone body사용: protein사용 절약
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The composition of blood
산소, 영양분, H운반: 기관통합
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Physiological effects of low blood glucose in humans
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The well-fed state: the lipogenic liver
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고혈당시
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The endocrine system of the pancreas
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Glucose regulation of insulin secretion by pancreatic β cells
혈당저하
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ATP-gated K+ channels in β cells
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ATP-gated K+ channels in β cells
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ATP-gated K+ channels in β cells
Sulfonylurea 결합 Channel 차단 인슐린 분비
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Sulfonylurea drugs: anti-diabetic
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The fasting state: the glucogenic liver
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공복시
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Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus
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Plasma concentrations of fatty acids, glucose, and ketone bodies during the first week of starvation
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위급한 상황, 도피
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Set-point model for maintaining constant mass
식욕억제
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Obesity caused by defective leptin production
ob/ob mice: leptin KO db/db mice: leptin receptor KO
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Hypothalamic regulation of food intake and energy expenditure
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Hypothalamic regulation of food intake and energy expenditure
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Hypothalamic regulation of food intake and energy expenditure
저장지방 소모
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Hormones that control eating
POMC 식욕촉진 식욕억제
Neuropeptide Y(NPY): ob/ob mice에서 증가
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The JAK-STAT mechanism of leptin signal transduction in the hypothalamus
식욕억제
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A possible mechanism for cross-talk between receptors for insulin and leptin
Insulin에 대해 더 민감하게
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The role of AMP-activated protein kinase (AMPK) in regulating ATP metabolism
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27.4 How is Overall Energy Balance Regulated in Cells? • AMP-activated protein kinase (AMPK) is the
cellular energy sensor • Metabolic inputs to this sensor determine whether its
output (protein kinase activity) takes place • When ATP is high, AMPK is inactive • When ATP is low, AMPK is allosterically activated
and phosphorylates many targets controlling cellular energy production and consumption
• AMPK is an αβγ heterotrimer; the α-subunit is the catalytic subunit and the γ-subunit is regulatory
• The β-subunit has an αγ-binding domain that brings α and γ together
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Figure 27.6 AMPK regulation of energy production and consumption in mammals.
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Formation of adiponectin and its actions through AMPK
지방조직에서 생성
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27.5 How Is Metabolism Integrated in a Multicellular Organism?
• Organ systems in complex multicellular organisms have arisen to carry out specific functions
• Such specialization depends on coordination of metabolic responsibilities among organs so that the organism as a whole can thrive
• Organs differ in the metabolic fuels they prefer as substrates for energy production (see Figure 27.7)
• The major fuel depots in animals are glycogen in live and muscle; triacylglycerols in adipose tissue; and protein, mostly in skeletal muscle
• The usual order of preference for use of these is glycogen > triacylglycerol > protein
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Figure 27.7
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27.5 How Is Metabolism Integrated in a Multicellular Organism?
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6) SIRT1 activator: Resveratrol Resveratrol is found in grapes, wine, grape juice, and berries of Vaccinum species including blueberries, bilberries, raspberries (覆盆子)and cranberries. Cell energy
demand [ATP]/[AMP]
Activation de l’ AMPK Resveratrol
SIRT 1
FOXO PPAR PGC-1 α
Energetic Metabolism
Release of fatty acids from adipose
tissue
Calorie Restriction
Food Serving Total resveratrol (mg) Peanuts (raw) 1 c (146 g) .01-0.26 Peanuts (boiled) 1 c (180 g) .32-1.28 Peanut butter 1 c (258 g) .04-.013 Red grapes 1 c (160 g) .24-1.25
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Mode of action of PPARs
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Metabolic integration by PPARs
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The Liver is the Major Metabolic Processing Center in Vertebrates • Most of the incoming nutrients that pass through the
intestines are routed via the portal vein to the liver for processing and distribution
• Liver activity centers around glucose-6-phosphate • Glucose-6-phosphate can be:
• converted to glycogen • released as blood glucose, • used to generate NADPH and pentoses via the
pentose phosphate pathway, • or catabolized to acetyl-CoA for fatty acid synthesis
or for energy production in oxidative phosphorylation
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Figure 27.11 Metabolic conversions of glucose-6-phosphate in the liver.
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27.7 Can You Really Live Longer by Eating Less? • Caloric restriction leads to longevity • For most organisms, caloric restriction results in
lower blood glucose levels, declines in glycogen and fat stores, enhanced responsiveness to insulin, lower body temperature, and diminished reproductive capacity
• Caloric restriction also diminishes the likelihood for development of many age-related diseases, including cancer, diabetes, and atherosclerosis
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Mutations in the SIR2 Gene Decrease Life Span • Deletion of a gene termed SIR2 abolishes the ability
of caloric restriction to lengthen life in yeast and roundworms
• This implicates the SIR2 gene product in longevity • The human gene analogous to SIR2 is SIRT1, for
sirtuin 1 • Sirtuins are NAD+-dependent protein deacetylases • The tissue NAD+/NADH ratio controls sirtuin protein
deacetylase activity • Oxidative metabolism, which drives conversion of
NADH to NAD+, enhances sirtuin activity
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SIRT1 is a Key Regulator in Caloric Restriction • SIRT1 connects nutrient availability to the expression
of metabolic genes • SIRT1 participates in the transcriptional regulation of
adipogenesis through interaction with PPARγ (peroxisome proliferator-activator receptor-γ)
• PPARγ is a nuclear hormone receptor that activates transcription of genes involved in adipogenesis and fat storage
• SIRT1 binding to PPARγ represses transcription of these genes, leading to loss of fat stores.
• Because adipose tissue functions as an endocrine organ, this loss of fat has significant hormonal consequences for energy metabolism
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SIRT1 is a Key Regulator in Caloric Restriction
Figure 27.13 The NAD+-dependent protein deacetylase reaction of sirtuins.
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Resveratrol in Red Wine is a Potent Activator of Sirtuin Activity
Figure 27.14 Resveratrol, a phytoalexin, is a member of the polyphenol class of natural products. It is a free-radical scavenger, which may explain its cancer preventive properties.
French people enjoy longevity despite a high-fat diet. Resveratrol may be the basis of this “French paradox”.
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Metabolic Syndrome (Syndrome X) : obesity, Type 2 diabetes, hyperlipidemia, hypertension, etc
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제1형 당뇨병과 제2형 당뇨병의 비교
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제2형 당뇨병에서 조직들간의 관계
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당뇨병의 주요 개념도
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"Lipid burden" hypothesis for the development of type 2 diabetes mellitus
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insulin
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Overview of metaboilsm
Glycogenesis Glycogenolysis
F-1,6-bisphosphatase
F-6-P
Phosphofructokinase
Phosphoenolpyruvate kinase((PEPCK) FOXO1,HNF-4
단백질합성
Pyr dehydrogenase
Chol synthesis
HMG-CoA reductase Cholesterol
PPAR α/β
PGC1 α
PKA
cAMP
GProtein
Glucagon Epinephrine
Akt GSK3β
GS
Glycogen 합성
PI3K
IRS
Insulin S70S6K
mTOR
Glut4
Glu
Glu
IR
SREBP-1,2
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PKA
CREB
PGC-1α
IRS
PI3K
FA합성 Chol합성 Glycogen합성
GSK3β
mTOR
S70S6K
S6protein
FOXO1, HNF-4 PPARα, β(δ)
gluconeogenesis β -oxidation
Fasting Diet
Akt
SREBP-1,2
Glucagon
cAMP
Insulin
CBP/p300
AMPK(AMP senser) Sirt1(NAD senser)
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• RIA원리, hormone release cascade • Glucagon, epi, insulin에 의한 glu, aa, FA 대사 조절 • 당뇨, 단식 시 대사변화, 당뇨병 • Leptin: JAK • Adiponectin: AMPK • POMC(a-MSH): 식욕억제 • NPY: 식욕촉진 • PPARs • Diabetes 치료약기전 • Hormone-signaling-대사
요약