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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