Download Liver- integrated lecture

Eva Samcová
• No fuels enters from the gut and little glycogen is left in the
liver
• Tissues which require glucose are dependent on hepatic
gluconeogenesis
• Cori and Alanine cycles play important role
• FA can not be used for synthesis of glucose (acetyl~CoA can
not be converted to glucose)
• Glycerol becomes important substrate for gluconeogenesis
• AA, which are hydrolyzed in skeletal muscle (especially),
supply most of the carbon atoms for net glucose synthesis
mostly in the for of Ala and Gln
• Most of Gln released from muscle is converted
(oxidized) into alanine and NH4+ by intestinal
epithelium and being released into
bloodstream (glutaminolysis –Gln,Glu,αketo,TCA,malate,pyr,transamination)
• Gluconeogenesis in the liver fasting is closely
connected with to urea cycle (ornithine,
carbamoyl phosphate, citrulline)
• AT – lipolysis is activated(low blood insulin),
blood level of fatty acids raises ad are used by
peripheral tissues (heart, muscle, liver –
formation of glucose and ketone bodies)
• FA oxidation in liver provide most of ATP needed
for gluconeogenesis
• Acetyl~CoA is mostly converted to ketone bodies
(small amount is oxidized completely)
• Ketone bodies and FA are preferred by many tissues
over glucose; they can also suppress proteolysis and
BCA oxidation in muscle
• Cooperation of tissues : liversynthesizes glucose,
muscle and gut supply the substrate (alanine), and AT
supplies the ATP (via FA oxidation in liver) needed for
gluconeogenesis
• This cooperation is dependent on levels of hormones
(insulin, glucagon, epinerphine)
• Reduction of triiodothyronine – reduces daily basal
energy requirements
Fasting State
• After fuel is again absorbed from gut
• Fat is metabolized like in well-fed state
• Liver remains in the gluconeogenic mode for a
few hours after refed, glucose formed by
gluconeogenesis is used in glycogenesis,
glucose is consumpted in peripheral tissues
and substrates from it are used by liver for
gluconeogenesis
• If rate of gluconeogenesis declines, glycolysis
becomes the predominant means of glucose
disposal in the liver
Metabolic interrelationship of major tissues
in the early refed state
• Blood glucose concentrations are controlled
within very tight limits
• Whereas FA and ketone bodies
concentrations in the blood can vary by one
or two orders of magnitude
• If blood glucose falls too low (<2 mM),
coma and death will follow shortly
• If hyperglycemia is set – dehydration
(glucose is lost in urine, urinary losses of
water, glucose and electrolytes) –
hyperglycemic, hyperosmolar coma
• Glucose homeostasis has 5 phases
Exercise
Anaerobic exercise : sprinting or weight lifting (very little organ
cooperation), muscle largely relies on its own stored glycogen
and phosphocreatinine
Aerobic exercise : long-distance running
is metabolically more interesting. For moderate exercise, much
of the energy is derived from glycolysis of muscle glycogencontent of it can be increased by exhaustive exercise that
depletes glycogen, followed by rest and a high-carbohydrate
diet. It is not enough glucose and glycogen for endurance
running – switching to fatty oxidation
The respiratory quotient (the ratio of CO2 exhaled to oxygen
consumed) falls during running-this indicates the progressive
switch from glycogen to fatty acid oxidation during the race.
Aerobic exercise
Stress
• Physiological stress : injury, surgery, renal failure, burns,
infections.
• Blood cortisol, glucagon, catecholamines increase. Basal
metabolic rate, blood glucose, and free fatty acids level are
elvated. Ketogenesis is not accelerated as in fasting, glutamine
pool in muscle is reduced, protein breakdown is increased.
• It has been proposed that the negative nitrogen balance (loss
of body proteins) of injured or infected patients is mediated
by monocyte and lymphocyte proteins, such as interleukin 1
(activates proteolysis), interleukin-6 (stimulates synthesis of
hepatic proteins –acute phase reactants), and TNF-α
(supresses adipocyte fat synthesis , prevents uptake of
circulating fat by inhibition of lipoprotein lipase, stimulates
lipolysis and inhibits release of insulin.
Stress
• The liver is primarily responsible for the first two steps of
ethanol catabolism
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• Liver disposes of NADH generated by this reaction only
in mitochondrial electron transport chain – ethanol
generates too much NADH
• Some enzymes are inhibited by NADH
(gluconeogenesis, -oxidation)
• The result is fasting hypoglycemia and accumulation of
TAG
• Fatty liver , cirhosis
• Redundant acetate is metabolized in peripheral tissue
• Formation of acetaldehyde adducts
Ethanol ingestion
Acidosis
• Regulation of acid-base balance – is shared by the liver and
kidney
• Metabolism of proteins generates excess hydrogen ions. The
kidney helps regulate blood pH by excreting H+ , which is
necessary for reabsorption of bicarbonate and ammonia in
tubular filtrate. Glutamine is precursor of renal ammonia
production. In chronic metabolic acidosis, the activity of renal
glutaminase, glutamate dehydrogenase, phosphoenolpyruvate
carboxykinase increase and correlate with increased urinary
secretion of NH4+ . Liver participates by synthesing less urea,
which makes more glutamine for kidney.
Acidosis