GI & Liver metabolism I&II Flashcards
xenobiotics
taking things in from the outside that are not part of your everyday routine
-ex. drugs, poisons
how does acetyl CoA get into the cytosol?
binds to OAA –> convert to citrate –> enter cytosol and broken down by citrate lyase to OAA and acetyl CoA –> start making FAs
Acetyl CoA
2C units
contains CoA - made from vit. B5 (pantothenic acid)
ACC (acetyl CoA carboxylase)
rate limiting
- starts FA synthesis
- activated by energy and citrate –> adds CO2 to acetyl CoA to make malonyl CoA
- deactivated by long chain FAs
- AMP-kinase (low energy) turns off through phosphorylation
- also short term regulation of TAG synthesis
biotin (vit. B7)
needed for most carboxylase enzymes
FA synthesis
- add 2C additions (acetyl groups) with fatty acid synthase –> 16C product
- anabolic process - requires reducing equivalents –> NADPH in cytosol
beta oxidation
- FAs enter mitochondria through carnitine shuttle
- inhibit CPT1 with malonyl CoA –> prevent FAs from entering mitochondria
how do you make TAGs?
FAs are esterified to glycerol
- liver - make glycerol3P from glycerol kinase or DHAP
- adipocytes - make glycerol3P if it is well fed and running glycolysis; NO glycerol kinase
- dehydration synthesis rxn
ChREBP (carbohydrate response element binding protein)
long term regulation of TAG synthesis
- activated by carbs to transcribe genes that make FAs (ex. FA synthase or ACC)
- inhibited by AMP & PKA
hormone sensitive lipase
breaks down (hydrolyzes) TAGs into free FAs and glycerol
- free FAs transported in blood to tissue by albumin
- glycerol goes to liver for gluconeogensis
how do you form ketone bodies?
2C acetyl groups –> 4C acetoacetate –> broken down into acetone or 3-hydroxybutyrate
- increased in fasting, carb restrict diets, or starvation
- production spares glucose
what happens if ketone body production is greater than use?
ketonuria or ketonemia
-can cause diabetic ketoacidosis –> pH can decrease
function of lipoproteins
transport fat throughout body
- chylomicrons - least dense
- HDL - most dense
how are most of the TAGs broken down?
pancreatic lipases
formation of bile salts
cholesterol –> 7alpha hydroxylase –> 7 hydroxycholesterol –> chenodeoxycholic acid or cholic acid
function of bile salts
- interact with FAs to form micelles
- emulsifying agents
- increase water solubility through conjugation of glycine or taurine in liver
mutation in 7 alpha hydroxylase enzyme
bile acid/salt disorder
- no bile salts –> no micelles –> poor fat absorption –> fatty stool
- cannot form bile salts –> build up cholesterol –> gallstones
role of CCK
- slow motility of stomach
- increase pancreatic enzymes
- GB contraction to release bile
role of secretin
-pancreatic release of bicarb to neutralize stomach acidity
bile salt deficiency disorder
making cholesterol faster than being converted into bile salts
-take oral bile salts (chenodeoxycholic acid) for treatment
what is needed for chylomicrons
ApoB48
- cholesterol on the inside, PLs on the outside
- TAG loading requires MTP to dock with ApoB48 or 100
- deficient MTP –> abetalipoproteniemia
role of lipoprotein lipase
found in the tissues
- activated by ApoCII to release FAs from chylomicrons
- FAs enter tissue
- glycerol goes back to liver
phase 1 liver detox rxn
fat soluble toxins
- cytochrome p450 enzymes
- try to make more water soluble
- substrate for phase 2
phase 2 liver detox rxn
water soluble toxins
- conjugation pathway –> sulfation, glucoronidation, GSH
- excreted as waste
acetominophin toxicity
metabolized by CYTp450 enzymes –> glucoronidation and sulfation
- detoxed by GSH
- alcohol –> reduces GSH leading to toxicity
- treat with n-acetylcystein (NAC) to boost GSH
function of cholesterol
- membrane fluidity
- forms bile salts and vitamin D
- precursor for steroids
- come from diet or synthesis in liver –> synthesized in cytosol w/ a lot of reducing equivalents
- 1/3 free in blood, 2/3 bound to lipoproteins (linoleic acid)
cholesterol absorption
- absorbed by intestinal micelles –> Niemann Pick C1
- inhibited by ezetimibe to lower cholesterol
- plant sterols excrete cholesterol in enterocytes
where do all Carbons come from during cholesterol synthesis?
acetyl CoA
-HMG-CoA –> mevalonate by HMG-CoA reductase (rate limiting step)
regulation of cholesterol synthesis
regulated by phosphorylation
- AMP, glucagon, sterols –> inactivate HMG-CoA reductase
- insulin, thyroid hormone, high ATP –> activate HMG-CoA reductase
what is the 5C unit of cholesterol?
dimethylallyl pyrophosphate
-formed from mevalonate
squalene synthase
catalyzes rxn from farnesyl pyrophosphate to squalene
-uses a lot of NADPH
function of statins
mimic HMG-CoA substrate for HMG-CoA reductase enzyme –> competitive inhibitor
-transition state analog
cholesterol and bile acids
- cholesterol –> primary bile acids (more water soluble through hydroxylation) - emulsification
- bacteria deconjugate primary to secondary
- liver conjugates bile acids with glycine or taurine –> more water soluble and ionized
ingested cholesterol transport from enterocyte
-taken up by chylomicrons (use ApoB48) –> lymphatics, thoracic duct, left subclavian
cholesterol transport from liver
-taken up by VLDL and LDL (use Apo100)
ApoB gene
makes ApoB48 and ApoB100
-deficiency –> abetalipoproteinemia
nonalcoholic fatty liver disease (hepatic steatosis)
imbalance b/w hepatic TAG synthesis and VLDL secretion
what shuttles cholesterol to liver or to peripheral tissues?
LDL
role of cholesterol ester transfer protein (CETP)
takes TAG from VLDL to put on HDL with the exchange of cholesterol
- VLDL forms LDL
- do this bc HDL removes cholesterol from periphery (lowering risk for atherosclerosis)
function of HDL
uses ApoA1 along with ApoC and ApoE
-reverse cholesterol transport –> take cholesterol from tissues back to liver
LCAT
used to add ester to cholesterol to put it into chylomicron core - make more room on outside for more cholesterol binding
-activated by ApoA1 on HDL
ABCA1 protein
used to help add cholesterol to HDL in the tissues
function of bile salts and fiber on cholesterol
lowers absorption of cholesterol by binding to and excreting it
phosphorylation
anabolic pathways –> turns off
catabolic pathways –> turns on
how is cholesterol regulated
long term by sterol response element (SRE) and sterol response element binding protein (SREP) –> controls expression of HMG CoA reductase expression
