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Nucleotide metabolism 대사의 주요 개념도
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
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
Signaling by the neuroendocrine system
E 대사기관
Epi, Ach
Radioimmunoassay (RIA)
Radioimmunoassay (RIA)
Two general mechanisms of hormone action
Insulin
Proteolytic processing of the pro-opiomelanocortin (POMC) precursor
식욕억제
NO
The major endocrine glands
The major endocrine systems and their target tissues
ng
ug
mg
CRH
Neuroendocrine origins of hormone signals
Neuroendocrine origins of hormone signals
Two hormones of the posterior pituitary gland
ADH
Cascade of hormone release following central nervous system input to the hypothalamus
Specialized metabolic functions of mammalian tissues
대사중심
Pathways of Carbohydrate, Amino Acid, and Fat Metabolism Illustrated in Earlier Chapters
Metabolic pathways for glucose 6-phosphate in the liver
Glucokinase Hexokinase
Metabolism of amino acids in the liver
식간 glu level 조절
Metabolism of fatty acids in the liver
-albumin
공복시심장(1/3), 뇌(2/3) E원
Adipocytes of white and brown adipose tissue
FIGURE 17-3 Mobilization of triacylglycerols stored in adipose tissue.
Distribution of brown adipose tissue in a newborn infant
Energy sources for muscle contraction
Slow-twitch muscle: Mt, 혈관 많음,적색근, ATP생성 지속적 Fast-twitch muscle: Mt, 혈관 적음, 백색근, ATP 사용 빠름
Metabolic cooperation between skeletal muscle and the liver: the Cori cycle
Glu- Ala cycle과 협력
Electron micrograph of heart muscle
심장: 1분에 6L혈액 분출, Mt 많음, Cr-p, 동맥경화,혈전 FFA, Glu, Ketone body E원
The fuels that supply ATP in the brain
막전위유지
Glucose metabolism in the brain
휴식시
불면시
Glu만 사용, 20%산소사용 Ketone body사용: protein사용 절약
The composition of blood
산소, 영양분, H운반: 기관통합
Physiological effects of low blood glucose in humans
The well-fed state: the lipogenic liver
고혈당시
The endocrine system of the pancreas
Glucose regulation of insulin secretion by pancreatic β cells
혈당저하
ATP-gated K+ channels in β cells
ATP-gated K+ channels in β cells
ATP-gated K+ channels in β cells
Sulfonylurea 결합 Channel 차단 인슐린 분비
Sulfonylurea drugs: anti-diabetic
The fasting state: the glucogenic liver
공복시
Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus
Plasma concentrations of fatty acids, glucose, and ketone bodies during the first week of starvation
위급한 상황, 도피
Set-point model for maintaining constant mass
식욕억제
Obesity caused by defective leptin production
ob/ob mice: leptin KO db/db mice: leptin receptor KO
Hypothalamic regulation of food intake and energy expenditure
Hypothalamic regulation of food intake and energy expenditure
Hypothalamic regulation of food intake and energy expenditure
저장지방 소모
Hormones that control eating
POMC 식욕촉진 식욕억제
Neuropeptide Y(NPY): ob/ob mice에서 증가
The JAK-STAT mechanism of leptin signal transduction in the hypothalamus
식욕억제
A possible mechanism for cross-talk between receptors for insulin and leptin
Insulin에 대해 더 민감하게
The role of AMP-activated protein kinase (AMPK) in regulating ATP metabolism
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
Figure 27.6 AMPK regulation of energy production and consumption in mammals.
Formation of adiponectin and its actions through AMPK
지방조직에서 생성
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
Figure 27.7
27.5 How Is Metabolism Integrated in a Multicellular Organism?
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
Mode of action of PPARs
Metabolic integration by PPARs
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
Figure 27.11 Metabolic conversions of glucose-6-phosphate in the liver.
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
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
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
SIRT1 is a Key Regulator in Caloric Restriction
Figure 27.13 The NAD+-dependent protein deacetylase reaction of sirtuins.
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”.
Metabolic Syndrome (Syndrome X) : obesity, Type 2 diabetes, hyperlipidemia, hypertension, etc
제1형 당뇨병과 제2형 당뇨병의 비교
제2형 당뇨병에서 조직들간의 관계
당뇨병의 주요 개념도
"Lipid burden" hypothesis for the development of type 2 diabetes mellitus
insulin
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
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)
• 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