Unit 6 - Cholesterol Metabolism I; Synthesis of Cholesterol, Bile Salts, and Acids Flashcards Preview

Molecular and Cellular Princples of Medicine > Unit 6 - Cholesterol Metabolism I; Synthesis of Cholesterol, Bile Salts, and Acids > Flashcards

Flashcards in Unit 6 - Cholesterol Metabolism I; Synthesis of Cholesterol, Bile Salts, and Acids Deck (26)

overall cholesterol structure

4 planar hydrocarbon rings (A-D) of steroid nucleus
-has 8 carbon hydrocarbon attached to C17 of D-ring
-hydroxyl group attached to C3 of A ring
-DB between C5/6 of B right
-most cholesterol in plasma is esterified to FA at C3, and this cholesteryl ester is even more hydrophobic than cholesterol


how much animal VS plant sterols are absorbed from diet?

40% of cholesterol
5% of phytosterols


what is beta-sitosterol?

plant sterol


what happens to plant sterols and excess cholesterol upon entering enterocytes?

actively transported back into intestinal lumen by 2 members of ATP binding cassette (ABC) family of transporters


what is sitosterolemia?

autosomal recessive condition where sterol transporters ABCG5 and ABCG8 are defective
-accumulated beta-sitosterol and cholesterol in enterocytes enter blood stream to cause increased cardiovascular morbidity


where is cholesterol made? where do the carbons come from? reducing equivalents? energy?

virtually all cells except RBCs in humans
-majority in liver, intestines, adrenal cortex, and reproductive tissues
-like FAS, all carbons from ACoA, while NADPH is reducing equivalents
-E from hydrolysis of thioester bond of ACoA and terminal Pi of ATP
-this happens on cytoplasmic surface of SER, and needs ER membrane and cytosolic enzymes


does the HMG-CoA synthase for cholesterol work in the cytosol or the mitochondria?

the cytosol


what is the key regulatory step for cholesterol synthesis?

HMG CoA reductase (integrated in SER facing cytoplasm)
-converts HMG CoA to mevalonate
-needs 2 NADPH, and CoA is released so irreversible
-inhibited by cholesterol


what is isopentenyl pyrophosphate (IPP)

made in 8-step pathway for mevalonate to cholesterol
-precursor for isoprenoids (dolichol, CoQ, vit K, cholesterol)


what are the 8 steps from mevalonate to cholesterol?

1. phosphorylation via 2 kinases (takes 2 ATP) = 6C
2. decarboxylation (takes 1 ATP, releases CO2) = 5C
3. isomerization = 5C
4. transferase (adds 1 IPP from 2) = 10C
5. transferase (adds 1 IPP from 2) = 15C
6. squalene synthase (adds 1 FPP from 5, needs 1 NADPH, releases 2 PPi and NADP+) = 30C
7. squalene monoxygenase (needs NADPH + O2, releases H2O and NADP) = 30C sterol
8. multistep reaction in ER = 27C cholesterol


what is smith-lemli-opitz syndrome?

an autosomal recessive disorder of cholesterol biosynthesis
-caused by partial deficiency in 7-dehydrocholesterol-7-reductase that reduces DB in 7-DHC to convert to cholesterol
-one of the several multisystem embryonic malformation syndromes associated with impaired cholesterol synthesis


how is HMG-CoA reductase regulated? proteins involved, areas involved, difference if low/high cholesterol, etc.

under control of transcription factor SREBP-2 (sterol regulatory element binding PRO 2) that binds cis acting SRE (sterol regulatory element)
-inactive SREBP-2 is integral ER membrane PRO that associates with ER PRO SCAP (SREBP cleavage activating PRO)
-when cholesterol levels are low, SREBP-2-SCAP complex moves to Golgi to cleave SREBP to soluble fragment (activated SREBP transcription factors)
--SREBP transcription factor enters nucleus, binds SRE, and stimulates HMG CoA reductase mRNA and enzyme expression
-when cholesterol levels are high, it binds to SCAP, which binds to more ER PRO insigs (insulin induced gene products) that anchor SREBP-2-SCAP to ER membrane, so can't go to Golgi and synthesis decreases


how is HMG-CoA reductase degraded?

when cholesterol levels are high, they bind to sterol-sensing domain of HMG-CoA reductase
-causes binding of reductase to insigs (as if SCAP was activated), and triggers ubiquitination and proteosomal degradation of enzyme, leading to reduced cholesterol biosynthesis


how does phosphorylation affect HMG-CoA reductase?

phosphorylated = inactive (AMP-activated protein kinase; if AMP is high and ATP is low)

dephosphorylated = active (phosphoprotein phosphatase; if AMP is low and ATP is high)


how do hormones affect HMG-CoA reductase?

insulin and thyroxine upregulate expression
glucagon and glucocorticoids downregulate expression


how do statin drugs work?

structural analogues of HMG, but with bulky hydrophobic groups
-serve as competitive inhibitors of HMG CoA reductase to lower cholesterol levels


how is cholesterol degraded?

ring structure not metabolized to CO2 and water in humans, but sterol nucleus is eliminated by conversion to bile acids and bile salts
-small percentage of cholesterol in feces or bile
--some is mmodified by intestinal bacteria before excretion


what are the primary products of cholesterol degredation?

isomers of coprostanol and cholestanol (reduced forms of cholesterol)
-along with cholesterol, these make up the majority of neutral fecal sterols


bile acid structure and what this means pH-wise

have steroid nucleus ring structure with 2-3 hydroxyl group sand a hydrocarbon side chain with terminal carboxyl group
-carboxyl group has pKa of 6 (matches duodenal pH) so 50% are protonated (bile acids) and 50% unprotonated (bile salts)
-OH groups are below plane of sterol ring (alpha); methyl groups are above (beta) so have polar and nonpolar faces


what are the 2 most common "primary" bile acids?

cholic acid (triol) and chenodeoxycholic acid (diol)


where does bile acid synthesis occur? what happens?

multistep process that involves multiple organelles in hepatic cells
-OH groups are added to ring, DB is reduced, and hydrocarbon chain is shortened by 3 carbons (has carboxyl group)


what is the rate limiting step of bile acid synthesis?

cholesterol-7-alpha-hydroxylase; adds hydroxyl group at C7 of cholesterol to convert to 7-alpha-hydroxycholesterol
-downregulated by bile acids


how do glycine or taurine conjugate bile acids?

before bile acids leave the liver
-amide bond forms between carboxyl group of bile acid and amino group of glycine (carboxyl) or taurine (sulfate) in 3:1 ratio
-lowers pKa, so bile salts are fully ionized at alkaline pH of bile, so better detergents


what forms of bile salts are in bile?

only the conjugated forms


what do intestinal flora do to bile salts?

remove glycine and taurine from conjugated form
-also can remove hydroxyl group from carbon 7 to make secondary bile acids


enterohepatic circulation of bile salts

0.5 g/day of primary and secondary bile salts (<3%) are lost in feces, and compensated for by liver synthesis
-the rest can be reabsorbed in terminal ileum by Na+-bile salt cotransporter, and returned to blood via different transpoter
-albumin binds and transports bile salts in blood
-hepatocytes take bile salts from blood with an isoform of Na+-bile cotransporter

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