B2.073 Central Role of the Liver in Metabolic Interrelationships Flashcards
what substrate is required to drive the citric acid cycle?
ADP
when does ADP increase?
metabolic demand and work increase
what is the net result of an ADP increase?
sum reaction of citric acid cycle and ETC increased to produce ATP for the increase in metabolic demand
what are the 2 consequences of a drop in ATP?
- need to stimulate catabolic processes to produce ATP
2. need to suppress anabolic processes that consume ATP
what substrate functions to suppress anabolic processes that consume ATP?
increase in AMP
activates AMPK
why does AMP rise when ATP falls?
increase in ADP triggers the sum reaction :
ATP > AMP + 2 Pi + energy
what is the relative size in ATP decline vs. AMP increase?
small fall in ATP produces very large increase in AMP
concentration of ATP in liver is much greater than AMP
this makes AMP a perfect sensor for energy status of the cell
what is the function of AMPK?
phosphorylation of key regulatory enzymes
increases catabolic pathways that produce ATP and inhibit anabolic pathways that consume ATP
describe the structure of AMPK
hetero-trimeric complex of alpha, beta, and gamma subunits
how is AMPK activated
activated by upstream kinases CaMKK and LKB1 via phosphorylation of threonine residue 172
what is activation of AMPK dependent on?
intracellular calcium and AMP/ATP ratio
how does AMPK affect skeletal muscle
- increases GLUT4 to promote glucose uptake
2. increase expression of PGC1a which stimulates biogenesis of mitochondria
how does AMPK affect the hypothalamus?
- appetite stimulation
how does AMPK affect the liver?
- inhibits acetyl CoA carboxylase and relieves inhibition of CPT1
- inhibits HMG CoA reductase which inhibits cholesterol synthesis
- inhibits expression of PEPCK
- inhibits mRNA translation/ protein synthesis
describe the structure of cholesterol
27 carbon multi ringed molecule
limited solubility
esterification of a fatty acid to the 3’ hydroxyl group produces a cholesterol ester
how does cholesterol affect membranes?
modulated fluidity more cholesterol = less fluid unesterified form (free form)
how are cholesterol esters stored?
fat droplets in adrenal gland, testes, ovaries
what is cholesterol a precursor for?
bile salts
steroid hormones
vitamin D3
where is cholesterol synthesized?
most cells have the capability except RBCS
very active process in liver, intestines, adrenal glands, testes, ovaries
give a brief overview of cholesterol synthesis
takes place in cytosol and ER
condensation of acetyl CoA and acetoacetyl CoA to form HMG-CoA
pools of HMG CoA in cytosol and mitochondria (cytosolic goes to cholesterol, mitochondrial goes to ketone bodies)
HMG-CoA reductase used to create Mevalonate and then cholesterol
major site of control of cholesterol synthesis
HMG-CoA reductase
how is HMG-CoA reductase regulated
transcription
phosphorylation by AMPK (turns off)
degradation
statins are inhibitors
how is cholesterol synthesis regulated by a feedback mechanism?
feedback inhibition by cholesterol at level of HMG CoA reductase
eat cholesterol = don’t make it
what protein is responsible for gene regulation of HMG CoA reductase?
SREBP2
when cells DONT HAVE cholesterol, SRBEP2 is transported from ER to Golgi
2 proteases S1P and S2P cleave the SRBEP2 into its mature form
mature form enters the nucleus and activates genes controlling lipid synthesis and uptake
chylomicrons
ApoE, ApoCII, ApoB48
synthesized in intestines to transport dietary fats
transports TAGs (85% of content) to peripheral tissues
remnants transport remaining TAGs and cholesterol to liver
VLDLs
ApoE, ApoCII, ApoB100
synthesized in liver
transport endogenous fats (50% TAGS, 20 % cholesterol, 20 % phospholipids)
converted to IDL and then LDL by lipoprotein lipase and interaction with HDL
LDLs
ApoB100
produced in plasma from VLDL through action of lipoprotein lipase, hepatic triacylglycerol lipase, and component exchange with HDL
transports cholesterol from liver to peripheral tissues
uptake by receptor mediated endocytosis in liver and peripheral cells
HDLs
ApoA, ApoE, ApoCII
synthesized in liver
transport cholesterol from peripheral tissues to liver
exchange of cholesterol ester for TAGs from VLDL and LDL mediated by cholesterol ester transfer protein (CETP)
what receptor mediates HDL cholesterol uptake in the liver?
scavenger receptor BI
describe the life cycle of an HDL
ApoA-1 synthesis in liver
ApoA-1 picks up cholesterol and phospholipids from macrophages
HDL3 results
HDL3 and HDL2 transfer some cholesterol esters to LDLs and VLDLs by CEPT
remaining HDL taken up by liver
what is the function of a statin?
upregulates receptors on cells to remove LDLs from the blood
inhibits cholesterol production
what is type 2 familial hypercholesterolemia?
defective LDL receptor
defective ApoB100
what is the result of type 2 familial hypercholesterolemia?
LDLs accumulate in blood and are consumed via the scavenger pathway
liver and peripheral cells cannot uptake LDLs so upregulate HMG-CoA reductase to make cholesterol for normal functions
what is the scavenger pathway for LDL uptake?
LDLs oxidized and combine with macrophages to form foam cells
located in subendothelial space of blood vessels
lead to plaque formation
what is NAFLD?
ectopic fat accumulation in the liver (hepatic steatosis)
what is insulin resistance?
decrease in target cells metabolic response to insulin
impaired lowering of blood glucose in response to insulin
how does insulin resistance start?
nutritional excess can cause chronic increase in blood glucose which causes chronic increase in insulin secretion which causes hyperinsulinemia which causes tissues to become resistant to action of insulin
what are some effects of insulin resistance?
glucose intolerance
NAFLD
DM2
subcutaneous fat
good fat, but capacity is limited
visceral fat
bell fat, bad fat
pathologic accumulation of fat
visual marker for ectopic fat accumulation
ectopic fat accumulation
pathologic accumulation of fat in other tissues (heart, liver, muscle, kidney, visceral)
fat makeup
primarily TAGs but contains a small about of DGs
DG is BAD activated protein kinases that interfere with insulin signaling
what is lipotoxicity
promotes oxidative stress and inflammation
what is “mixed insulin sensitivity”
glucose synthesis is not effectively inhibited by insulin
fat synthesis STILL promoted by insulin
result: fasting hyperglycemia, hepatic steatosis
what is the mechanism responsible for mixed insulin sensitivity
separate insulin signaling pathways control lipogenesis and gluconeogenesis
pathways controlling lipogenesis is intact in DM2
gluconeogenesis pathways is defective in DM2
have hypertriglyceridemia and hyperglycemia in the face of hyperinsulinemia
how is ethanol metabolized?
metabolized primarily by alcohol dehydrogenase which is expressed in highest amounts in the cytoplasm of the liver
what is the effect of ethanol metabolism on the NAD+ redox state?
highly reduced cytoplasmic NAD+ redox state
most of NAD+ is converted to NADH
low ratio of NAD+/NADH
what is the effect of ethanol metabolism on gluconeogenesis?
low ratio of NAD+/NADH reduced the concentration of pyruvate because
lactate + NAD+ <>pyruvate + NADH + H+
and pyruvate is shifting back to lactate to try to increase NAD+
what is the effect of acetaldehyde on the cell?
very reactive
metabolized in mitochondrial matrix
drives low ratio of NAD+/NADH in mitochondrial space
reduces rate of fatty acid oxidation bc you need NAD+
what is the mechanism for alcohol induced fatty liver?
- inhibition of gluconeogenesis by ethanol reduces blood glucose
- reduction of blood glucose lowers blood insulin and increases counter reg hormones
- low insulin promotes lipolysis in adipose
- increase in serum FFAs increases fatty acid uptake by liver
- inhibition of fatty acid oxidation by ethanol promotes fat accumulation in liver
how do chronic alcohol abuse and hyperglycemia affect tissues in the same manner?
both can result in AGE production and ROS damage
