Transcript Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox
LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
Fifth Edition
CHAPTER 23
Hormonal Regulation and Integration of
Mammalian Metabolism
© 2008 W. H. Freeman and Company
In the context of whole organism, hormonal signals integrate and coordinate the
metabolic activity of different tissues and optimize allocation of fuels and precursors.
The coordination of metabolism is achieved by
neuroendocrine system.
In neuronal signal, electrical signals (nerve
impulses) originate in the cell body of a neuron
and travel very rapidly over long distances to
the axon tip, where neurotransmitters are
released and diffuse to the target cell. The
target cell (another neuron, a myocyte, or a
secretory cell) is only a fraction of a micrometer
or a few micrometers away from the site of
neurotransmitter release.
In the endocrine system, hormones are
secreted into the bloodstream, which carries
them throughout the body to target tissues that
may be a meter or more away from the
secreting cell. Both neurotransmitters and
hormones interact with specific receptors on or
in their target cells, triggering responses.
The structure of thyrotropin-releasing hormone (TRH)
Purified (by heroic efforts, 20t hypothalamus from two million sheep) from
extracts of hypothalamus, TRH proved to be a derivative of the tripeptide Glu–
His–Pro.
Hormone act through high specific cellular receptor
1. Hormone and receptor are encounter in
extracellular space, cytosol, and nuclei.
2. Six general consequences:
1) A second messenger (cAMP) is generated
2) A receptor Tyr kinase is activated
3) A receptor guanylyl cyclase is activated
4) Change in membrane potential resulted in closing
or opening ion-channel
5) Convey information to cytoskeleton
6) Change in gene expression by steroids
3. Water soluble peptide and amine hormone act
extracellular through surface receptor.
 receptor serve as a signal transducer and
amplifier.
 very rapid response : lead to a change in the
activity of one or more preexisting enzyme
4. Water insoluble hormone (steroid, retinoid, thyroid)
pass through the plasma membrane to reach their
receptor proteins in the nucleus. alter gene
expresssion  slow response
Hormone can classified into
Endocrine: hormones are release into the blood and carried to target tissue
Paracrine: hormones are release into the extracellular space and diffuese to neighboring
target cell
Autocrine: hormones affect the same cell that releases them.
Peptide hormones: 3 to 2000 or more amino acid; insulin, glucagon, and somatostatin;
precursor to active form; release by exocytosis; a large amount of hormone release
suddenly; bind to receptor; generate second messenger
Insulin : preproinsulin (singnal p.p.)  proinsulin (secretary vesicle in pancreatic bcell)  Insulin
Prohormone proteins produce several active hormones. Pro-opiomelanocortin (POMC)
Catecolamine hormone: water soluble compound epinephrine and norepinephrine;
produced in brain as neurotransmitter and in endocrine hormone in adrenal gland;
stored secretary vesicle; exocytosis; bind to receptor; generate second messenger
Eicosanoid hormones: not synthesized in advance and stored; produced from
arachidonic acid, when they need; most cell produces these hormone and most cell can
respond by receptor; paracrine hormone; PG (muscle contraction, pain, inflammation);
Tbx (platelet aggregation), LTE (muscle contraction)
Steroid hormones: from cholesterol; endocrine; corticosteroid from adrenal cortex;
glucocorticoid (metabolism of carbohydrate), mineralocorticoid (regulate the
concentration of electrolytes in the blood, androgen(testosterone) from testes and
estrogen from ovaries; act through nuclear receptor
Vitamin D hormone: carcitriol (Ca2+ homeostasis in blood and bone); produce in liver
and kidney; diet or photolysis in skin; acting through nuclear receptor; up-regulation of
Ca2+ binding protein in intestine and uptake; bone disease
Retinoid hormone: regulate the growth, survival, and differentiation of cells via nuclear
retinoid receptor; from b-carotene; in liver; Excess can cause birth defect; pregnant
woman are advised not to use the retinoid creams.
Thyroid hormone: Tyr residue are enzymatic ally iodinated in the thyroid gland ; act
through nuclear receptor; stimulate energy-yielding metabolism by increasing the
expression of key metabolic enzyme.
Nitric oxid (NO): synthesize from arginine and molecular oxygen by NO synthase;
paracrine; entering the target cell and increase cGMP.
Hormone release is regulated by a hierarchy of neuronal and hormonal signal
1. The central nervous system receives input from many internal and external sensors
and then orchestrates the production of appropriate hormonal signal by endocrine
tissues
1) Hypothalamus
- coordination center of the endocrine system
- it receives and integrates messages from the central nervous system
- the hypothalamus produce regulatory hormones (releasing factor) that
pass directly to pituitary gland
2) Posterior pituitary gland
- axonal endings of many neurons originated from the hypothalamus
- these neuron contains short peptide hormones; oxytocine and
vasopressin
- upon stimulation, hormones in secretory granule are released
3) Anterior pituitary gland
- produce tropic hormones or tropins
- These peptides activate next level of endocrine glands, such as adrenal
cortex, thyroid gland, ovaries, testes
The major endocrine glands
Cascade of hormone release following central
nervous system input to the hypothalamus.
1. In each endocrine tissue along the
pathway, a stimulus from the level
above is received, amplified, and
transduced into the release of the
next hormone in the cascade.
2. The cascade is sensitive to
regulation at several levels
through feedback inhibition by the
ultimate hormone (in this case,
cortisol). The product therefore
regulates its own production, as in
feedback inhibition of biosynthetic
pathways within a single cell.
Specialized metabolic functions of mammalian tissues.
The Liver Processes and distributes nutrients
1. The liver has two main cell types
- Kupper cells: phagocytes, important in immune function
- Hepatocytes: transform dietary nutrients into the fuels and precursors required by
other tissues and export them via the blood.
2. Sugars
- GLUT2 : glucose transporter of hepatocytes
- Glucokinase : high Km for glucose, not inhibited by G-6-P
- Phosphorylation of glucose in hepatocyte is minimal, when glucose concentration
is low, preventing the liver from consuming glucose as fuel via glycolysis
Metabolic pathways for glucose 6-phosphate in the liver
1.
2.
3.
4.
5.
Dephosphorylation of G-6-P:
replenish blood glucose
Glycogen synthesis
Pyruvate dehydrogensase reaction:
yield energy
Incorporate into f.a or cholesterol
PPP for yield reducing power ,
needed for f.a or cholesterol and
ribose-5-p, a precursor for
nucleotide biosynthesis
Metabolism of amino acids in the liver.
1.
Produce its own protein: high
turnover rate or synthesis plasma
protein
2. Pass to other organ to synthesis their
own protein
3. Precursors for nucleotides, hormone,
other nitrogenouse compounds
4. Degrade into pyruvate and TCA
cycle intermedidate; Urea cycle
5. Pyruvate to glucose or glycogen
6. Pyruvate to acetyl Co A
7. Oxidation via TCA cycle
8. Oxidative phosphorylation
9. Convert to lipid
10. Glucose from TAC intermediates
11. Ala from muscle to liver and covert
to pyruvate to blood Glc (Glc-Ala
cycle)
Metabolism of fatty acids in the liver.
1.
2.
3.
4.
5.
6.
7.
8.
Convert to liver lipid
Act as a primary oxidative fuel in the
liver and oxideze to yield to acetylCoA and NADH
Further oxidize in TCA cycle
ATP generation
Ketone bodies
Cholesterol, steroid hormones, bile
acid
Convert to TAGs of plasma
lipoprotein
Fatty acids are bound to serum
albumin and carried to heart and
muscle, used as a major fuel
Thus liver act as 1) body’s distribution
center 2) detoxification
1.
1)
2)
3)
White adipocyte
Located in under the skin, around deep blood vessel, and the abdominal cavity
Filled with single large lipid
Metabolically active: glycolysis, TCA cycle, oxdative phosphorylation, synthesis of TAGs
(much of TAG is synthesized from liver, transported to adipocyte, stored in adipocytes
4) The release of f.a from adipocyte by epinephrine  activate lipolysis
5) Glycerogenesis
Brown adipocyte
1.
2.
3.
4.
5.
Stored TAG
More mitochondria and capillaries
Thermogenin, the mitochondrial
uncoupling protein thermogenesis
In fetus, preadipocyte is
differentiated into BAT to generate
heat
At birth, predipocyte is differentiate
in to WAT
Energy sources for muscle contraction
1.Muscle is specialized to generate ATP as the immediate source of energy for contraction
2. Two types: Slow-twitch muscle (red muscle) and Fast-twitch muscle (white muscle)
3. Resting muscle: f.a from adipose tissue and ketone bodies from liver
Moderately active muscle: f.a + k.b + blood glucose
Active muscle: anaerobic fermentation using stored muscle glycogen. Then use
phosphocreatine
After a period of intense muscular activity,
breathing heavily for supply oxygen for
oxidativative phosphorylation in liver.
The ATP produced is used for gluconeogenesis
from lactate and returned to muscle to
replenish their glycogen (Cori cycle)
4. Heart muscle: aerobic metabolism; mainly
fatty acid as a fuel; small amount of
glycogen, lipid, and phosphocreatine,
must keep supplying oxygen
The brain uses energy for transmission of electrical impulse
1. Adult brain use only Glc as fuel; active respiratory metabolism (use 20% of oxygen), little
glycogen, dependent on blood Glc
2. Brain can use b-hydroxybutyrate as fuel in starvation condition.
3. Energy is required to create and maintain an electrical potential across the membrane (Na+K+ ATPase).
Blood carries oxygen, metabolite, hormones
Role: 1) transport nutrients from small intestine
to liver 2) transport waste products from
exatrhepatic tissue to liver and to kideny
for excretion 3) transport oxygen 4)
carries hormonal signal.
Hormonal regulation of Fuel metabolism (Insulin)
1.
2.
3.
4.
5.
Stimulate Glc uptake by muscle and adipose tissue.
Stimulate synthesis of TAG in adipose tissue
In liver, activates glycogen synthase and inactivate glycogen phosphorylase.
In liver, activate glycolysis and formation of acetyl-CoA. If not further oxidized, acetyl-CoA
convert to TAG and transport to adipose tissue
In summary, the effect of insulin is to favor to the conversion of excess blood glucose to two
storage form, glycogen (in liver and muscle) and TAG ( in adipose tissue)
Glucose regulation of insulin secretion by
pancreatic b cells.
Hormonal regulation of Fuel metabolism (Glucagon)
1.
2.
3.
4.
Stimulate the net breakdown of glycogen by activating glycogen phosphorylase and inactivating
glycogen synthase.
Inhibits glycolysis and stimulate gluconeogenesis.
In adipose tissue, activating TAG breakdown free f.a, which exported to the liver and other
tissue for fuel.
The net effect of glucagon is to stimulate glucose synthesis and release by the liver and to
mobilize f.a from adipose tissue, to be used instead of glucose by tissues other than brain.
During fasting and starvation, metabolism shifts to provide fuel
for the brain
1.
2.
Fuel reserve as glycogen (liver), TGA (adipose tissue), and tissue protein
Glycogen (in 2 h)  TGA (in 4 h)  prolong starvation, to provide glucose for the brain
1.
2.
3.
4.
Cortisol is released by various stressor ( fear, pain, low blood Glc etc.)
Cortisol is relatively slow acting hormone that alters metabolism by changing the amounts
and kinds of enzymes
F. A release, breakdown muscle protein for gluconeogensis, stimulating the synthesis of
PEP carboxykinase
The net effect is to restore blood Glc to nomal level and to increase glycogen stores, ready
to support the fight or flight response.
Obesity and the regulation of body mass
The body can deal with an excess of dietary calories in three way:1)
convert excess fuel to fat and store it in adipose tissue 2) burn excess
fuel by extra exercise 3) waste fuel by diverting it to heat production
1. When the mass of
adipose tissue increases
(dashed outline),
released leptin inhibits
feeding and fat synthesis
and stimulates oxidation
of fatty acids.
2. When the mass of
adipose tissue decreases
(solid outline), a lowered
leptin production favors a
greater food intake and
less fatty acid oxidation.
1.
2.
3.
4.
Adiponectin: a peptide hormone, produced by adipose tissue, increase
uptake of fatty acid from the blood by myocyte and rate of b-oxidation in
muscle; block fatty acid synthesis and gluconeogenesis
Adiponectin triggers activation of AMPK.
AMPK shift metabolism from biosynthesis to energy production.
AMPK inactivate acetyl-CoA carboxylase.
Diet regulates the expression of genes central to maintaining body
mass
PPARs are transcription
factors that, when bound to
their cognate ligand (L), form
heterodimers with the nuclear
receptor RXR. The dimer
binds specific regions of DNA
known as response elements,
stimulating transcription of
genes in those regions.
Final exam.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
4 problems from mid-term exam without chemical structures
Figure 18-10 including chemical structures
Figure 18-15
Figure 19-19
Figure 19-29, 29-30, Table 19-5
Figure 19-56
Figure 20-14
Figure 21-6
Figure 23-8
Figure 23-13, Figure 23-14, Figure 23-15
Table 23-3
Table 23-4
Table 23-6
Enzyme cofactors
Grade: 70 (mid-term (100) + final (200)) + 30 (attendance + E.P in symposium)
Over 90 : A+; 85-90 : A0; 80-85: B+; 70-80: B0; 60-70: C+; below 60: C0