BC 36 Cholesterol Homeostasis Flashcards
Cholesterol Homeostasis (influx and efflux from body)
Influx:
- dietary cholesterol
- denovo synthesis from other tissues
- denovo from LIVER
Efflux:
- Free Chol
- Bile Salts (5% excreted)
- component of VLDL
DeNovo chol synthesis
location (tissue)
when
steps
made during the FED state with high IG ratio, requires lots of ATP and NADPH
AcCoA->HMG CoA->Mevalonic Acid->Chol Syn
Made in all tissues but particularly in LIVER, intestine, Adrenal Cortex and rep. tissue
Three major steps
I Synthesis of HMGcoA
II Synthesis of Mevalonic Acid
III Cholesterol Synthesis
Phase I of Denovo Chol Synthesis
Acetyl CoA to HMG CoA
Enzyme: cytosolic HMG CoA Synthase
Energy Carrier NADPH
The mito isoenzyme HMG CoA synthase is the RL step for Ketogenesis, but were talking about cytosolic
Phase II of Denovo Chol Synthesis
HMG-CoA -> Mevalonic Acid
Enzyme: Cytosolic HMGCoA reductase RATE LIM
-SER associated
Energy Carrier: NADPH
REGULATION: P & GE
-dephos-increase Activity high IG
GE: low cytosolic Chol-increased GE
Phase III of denovo Chol Synthesis
Mevalonic Acid->->->Cholestrol
-19 enzymes
energy carriers: NADPH and ATP
Three regulations of Cytosolic Cholesterol Homeostasis
- de novo synthesis (hmg co a reductase)
- endocytosed LDL (LDL receptor)
- ACAT enzyme (CE storage)
NONE of these dietary
Methods of Cholesterol Elimination (2)
FYI- ring structure CANNOT be catabolized to CO2 and H2O
-1gram excreted daily
- Chol converted to Bile Acids and then Bile Salts
(5% of salts excreted in feces) (0.5g worth of chol)
-bile salts provide ONLY sig mechanism for cholesterol excretion both as metabolic product and chol in bile - Free Chol secreted into bile
- 0.5g solubilized in bile and excreted as Free Chol
Phase 1 of Bile acid synthesis from cholesterol
Ph 1
Hydroxylation: Bile Acid Synthesis
Cholesterol 7 alpha hydroxylase (RATE LIM) is a cytochrome P450 monooxygenase
-places a hydroxyl group added at position 7 of steroid ring
regulation
- inhibited by cholic acid (feed back inh)
- activated by cholesterol
the intermediate (7ahydroxylcholesterol) is eventually converted to primary bile acids-cholic and chonodeoxycholic acid
BILE ACIDS MORE HYDROPHILIC THAN CHOL
Phase 2 of bile acid synthesis from cholesterol
conjugation of bile salt synthesis
-bile acids conjugated with glycine or taurine
-glycocholic acid, taurochenodeoxycholic acid
BILE SALTS MORE HYDROPHILLIC THAN CHOL
-better emulsifiers (enhanced amphipathy)
Action of intestinal flora
dehydroxylation of primary acids- primary acids reabsorbed by the liver with ease
cholic acid-> deoxycholic acid
chenodeoxycholic acid-> lithocholic acid
Enteropathic circulation
bile salts secreted into bile ->through duodenum where some converted to bile acids (via dehydroxylation by flora)->subsequent return to liver as mixture of acids and salts
5% of bile salts synthesized denovo (thats all thats lost)
Statins
Drug for hypercholesteremia
HMG CoA reductase inhibition
- structural analog of enzyme
- reversible competitive inh
lovastatin/simvastatin
Decrease donovo snythesis
- decrease cytosolic Chol
- increase LDL receptor synth
- increase LDL rec mediated endocytosis
- decrease serum LDL-C
Cholestyramine
Bile acid sequestration RESIN
+ charged rein forms ionic bonds with bile acids
- they can then be excreted
- reduced reabsorbtion
- decrease cytosolic chol
- increase LDL receptor synth
- -increase HMG coA reductase
- increase LDL rec med endo
- decrease Serum LDL-C
need ot be used in combo with another drug bc they increase HMG coA reductase
Cholesterol Absorbtion inhibitors
trying to reduce dietary input
Ezetimibe
binds to protein crucial for chol absorbtion located on GI epithelium as well as hepatocytes
- decrease cytosolic chol
- increase LDL receptor synth
- -increase HMG coA reductase
- increase LDL rec med endo
- decrease Serum LDL-C
need ot be used in combo with another drug bc they increase HMG coA reductase
Familial Hypercholesterolemia Type II Hyperlipidemia
Autosomeal DOMINANT -heterozygotes manifest
-more in homo
Defect in LDL receptor
- NO LDL serum endocytosis
- serum LDL increase, less endocytosed, HMG CoA reductase increases synthesis
increase in LDL (tag normal level)
Xanthomata on Extremeties- acc of chol masses
-corneal arcus- opaque gray/white circumfrance in eye, cornea)
Atherosclerosis
Heart disease
COMBO drug therapy
