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
What 2 types of enzymes are required for conversion of chol to steroid?
CYP (membrane-bound, in ER or IMM) and side-chain DH (cytosol or ER)
What is aromatase? What does it do?
A CYP hydroxylase, cleaves C-C bond, “aromatization” of neutral sterol A ring; converts testosterone to estradiol
How are cortisol and cortisone interconverted?
Sol to sone: 11b-hydroxysteroid DH converts hydroxyl to keto (oxidase)
Sone to sol: reductase
What are the 2 isoforms of 11b-hydroxysteroid DH?
Type 1 (liver): bidirectional, potential to restore cortisone to active cortisol Type 2 (kidney): unidirectional to inactivate cortisol to cortisone
What are the two levels of steroid production control?
Acute control at level of substrate (chol) mobilization & long-term at level of gene transcription; both under control of trophic protein hormones
What is ACTH? LH, FSH? AT-2?
ACTH: regulates glucocorticoid biosynthesis
LH/FSH: reg gonadal hormone biosynth
AT-2: regulates mineralocorticoid synth
What is the first step in steroid hormone synthesis?
Conversion of chol to pregnenolone by side chain cleavage (P450scc); in mito, cytosolic export
How do trophic hormones affect steroid hormone production?
Interact with PM receptors to form cAMP (ATP hydrolysis), activates PKA -> CE hydrolase, StAR (steroidogenic acute protein) post-tln mod; FC -> IMM via cytoskeletal proteins (to OMM) and StAR (to IMM)
What is the limiting step in steroid synthesis?
Translocation of cholesterol between OMM and IMM, controlled by StAR activity
What is lipoid congenital adrenal hyperplasia (lipoid CAH)? How is it treated?
Loss of fxn StAR -> large adrenals full of CE, hyponatremia and -kalemia, phenotypically female regardless of gonadal sex
Tx: mineralo- and gluco-corticoid replacement therapy
What is vitamin D3 and D2?
D3: cholecalciferol (natural) produced in skin under UV light
D2: ergocalciferol formed in plants by UV irradiation (supplement in milk)
How are D vits activated?
In liver, D3 hydroxylated in O2-requiring rxn -> 25-HCC
In kidney, 25-HCC hydroxylated by mito oxygenate to active 1a,25-DHCC
Why is vit D important in Ca homeostasis? What is vitamin D intoxication?
Increases serum Ca by promoting int abs and stimulating release from bone; high serum Ca -> calcification soft tissues (kidney stone, bone demineralization)
