Block 3 Cholesterol Derivatives Flashcards
In what form is cholesterol excreted?
Bile acids and salts, mechanism: metabolic product of cholesterol or solubilizer of free cholesterol excretion in bile
How are bile acids synthesized?
In liver, 15 steps requiring 4 organelles (last is perox)
What is the difference between the classic/neutral and alt/acidic pathway of bile acid synthesis?
Classic: bio-transformation of sterol nucleus occurs before side chain mods
Acidic: side chain mods before mods of sterol nuc
Describe the classical pathway of BA synthesis.
Hydroxylation in 7a position of chol B ring, catalyzed by CYP7A; inhibited by BA (major reg); then saturate 5,6 =, epimer 3b-OH to a, add OH to 12a of C ring, 3C cleave side chain, ox C24 to carboxylate
What is farnesyl X receptor?
FXR inhibits CYP7A
What are the primary bile acids?
Chalk acid and chenodeoxycholic acid (weak acids, can pass into enterocyte by passive diff)
What are bile salts?
Bile acids further conjugated by the liver (with glycine pK 4, taurine pK 2); lower pK makes salt more ionic = better emulsifying (^ amphipathic), trapped in lumen (-), active transport reabsorption
How are bile salts synthesized?
Cholic acid + ATP + CoASH -> cholyl-CoA + taurine or glycine in amide linkage -> tauro- or glyco-cholic acid
What are secondary bile acids?
Bile salts modified by bacterial flora, removal of glycine/taurine and OH at C7; less soluble, less readily reabsorbed from lumen -> excretion
What is enterohepatic circulation?
Recirculation of bile acids 10-20x/day; reabsorbed from int lumen -> liver via portal vascular system; 5% eliminated, 6-800 ml bile produced/day (1.5-4g)
What is bile?
Complex aqueous mixture with non-lipids like organic an/cations, neutral amphipaths, lipids like bile acids, chol, PLs (mainly PC)
What kind of receptors mediate secretion of specific bile components? How are they regulated?
ATP-binding cassette (ABC) family of transporters; reg by liver X receptor (LXR)
Which transporters secrete PLs? BAs? Chol?
PL: ABCB4, MDR3
BA: ABCB11
C: ABCG5/8 (same as enterocyte)
How is a biliary micelle formed?
Bile salt from ABCB11 in bile interacts with B4 and G5/8 -> micelle
How do bile salts affect mixed micelles?
Drive C and PL (makes C soluble, prevents crystals, protects cells lining biliary tree from toxic action BS) secretion, stabilize micelles
How are gallstones formed?
C/PC ratio increases from canalicular space to bile ducts to gallbladder -> C crystal; overproduction hydrophobic BS (deoxycholate), GB hypo motility, mucin hypersecretion
How do GB hypo motility and mucin hyper secretion lead to gallstone formation?
GB: chol over-secretion increase resident time, allows nucleation chol -> crystal
Mucin: mucin gel matrix provides scaffold for crystal
What is cholesterol gallstone disease called? How is it treated?
Cholelithiasis; tx administer chenodeoxycholic acid (may take months/y to dissolve) or surgical removal
What are the roles of bile acids?
Excretion of chol, facilitate int absorption dietary TG and liposoluble vits
What are the compensatory mechanisms against elevated chol?
Reduced absorption chol, increase in BA synth, reduced ability fibroblasts to synth chol
What are the five main classes of steroid hormones?
Progestins, glucocorticoids, mineralocorticoids, androgens, estrogens
Where are gluco and mineralocorticoids produced? What are the major functions? What are common examples?
Adrenal gland; cortisol and aldosterone; maintenance of carb metab, stress management, salt balance
Where are progestins and estrogens produced? What are the major functions? What are common examples?
Ovary and placenta; progesterone, estradiol; induce secondary sex characteristics, essential for reproduction
Where are androgens produced? Major functions? Common example?
Testis; testosterone; maintenance of reproductive function, secondary sex characteristics
