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Cholesterol Derivatives, Bile Acid Synthesis-15 steps -in liver, using 4 diff. organelles -2 types: Classical(neutral)-70-95% of total Alternative(acidic)-in path. states -like adv. cirrhosis, biliary atresia Bile Acid Pool Chol/PL should be 0.3-1.0->stone if outside range Overproduction of hydrophob. salts Chol. oversecretion->gallbladder hypomotility Mucin Hypersecretion-provides scaffold to crystallize ALL LEAD TO GALLSTONE-chol. crystals ->cholelithiasis - Tx w/ surgery or chenodeoxycholic acid -> slow dissolution, Bile Acid Synthesis-15 steps -in liver, using 4 diff. organelles -2 types: Classical(neutral)-70-95% of total Alternative(acidic)-in path. states -like adv. cirrhosis, biliary atresia Bile Acid Pool Contains: Non-lipid- salts (stabilize mixed micelles) organic anions, cations, neutral amphipaths Lipid- bile acids-drive PL, Cholesterol secretion -help absorption of dietary TGs, liposol vitamins cholesterol-major excretion route phospholipids (PC)-help solubilize chol, protect lining Secretion via canalicular membrane receptors: Phospholipids: ABC-B4, MDR3 Bile Acids: ABC-B11 Cholesterol: ABC-G5/8 (same as enterocyte), 5 Categories, all w/ sterol nucleus: Adrenal Gland- 1. Glucocorticoids-cortisol (stress management, carb. metabolism) 2. Mineralocorticoids-aldosterone (salt balance) Ovary/Placenta- 3. Progestins-progesterone (reproduction, sex characteristics) 4. Estrogens-estradiol (reproduction, sex characteristics) Testis- 5. Androgens-testosterone (maintain reproductive fcn, 2° sex char.) Synthesis Control of Steroid Synthesis -Acute-cholesterol mobilization step -Long-term-gene transcription, Cholesterol Derivatives Steroid Hormones 5 Categories, all w/ sterol nucleus: Adrenal Gland- 1. Glucocorticoids-cortisol (stress management, carb. metabolism) 2. Mineralocorticoids-aldosterone (salt balance) Ovary/Placenta- 3. Progestins-progesterone (reproduction, sex characteristics) 4. Estrogens-estradiol (reproduction, sex characteristics) Testis- 5. Androgens-testosterone (maintain reproductive fcn, 2° sex char.), Cholesterol Derivatives Bile Acids/Salts Bile Acid Synthesis-15 steps -in liver, using 4 diff. organelles -2 types: Classical(neutral)-70-95% of total Alternative(acidic)-in path. states -like adv. cirrhosis, biliary atresia, Cholesterol Derivatives Vitamin D Sterol Derived Hormones Two D vitamins w/ identical biological action -diff groups off sterol nucleus D-ring -UV radiation opens B-ring Vit. D stays in body, Sterol Derived Hormones Two D vitamins w/ identical biological action -diff groups off sterol nucleus D-ring -UV radiation opens B-ring Vit. D stays in body Vitamin D Intoxication High Vit D intake over long periods ->high serum Ca++ ->Aberrant calcification of soft tissues: kidney stones, bone demineralization, Bile Acid Synthesis-15 steps -in liver, using 4 diff. organelles -2 types: Classical(neutral)-70-95% of total Alternative(acidic)-in path. states -like adv. cirrhosis, biliary atresia Classical 1st step:hydroxylate 7-alpha of B ring in cholesterol -via 7a-hydroxylase (CYP7A) -MAJOR REG. STEP -feedback inhibition (bile acids), Sterol Derived Hormones Two D vitamins w/ identical biological action -diff groups off sterol nucleus D-ring -UV radiation opens B-ring Vit. D stays in body Vitamin D2 Ergocalciferol -formed in plants under UV irradiation -in milk, Bile Salt Formation in liver-amphipathic -Further conjugate 1° acid with: Glycine-pKa~4 Taurine-pKa~2 (has sulfate) -add onto carboxylate group -adults: 3:1 glycine:taurine -kids 1:1 With lower pKa, salt is more ionic -more amphipathic->better emulsifier -trapped in lumen as (-) form -reabsorbed by active transport Mechanism 1. Activate 1°acid w/ ATP/CoASH -make e.g. Cholyl CoA 2. Amide linkage to Taurine, glycine ->tauro-, glycocholic acids ->tauro-, glycochenodeoxycholic acids