2- Cholesterol metabolism.pdf

Cholesterol and Steroid Metabolism BCH 440: Metabolism-II  Overview O Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of essential functions in the body not Cholesterol is a structural component of hand...

Cholesterol and Steroid Metabolism BCH 440: Metabolism-II  Overview O Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of essential functions in the body not Cholesterol is a structural component of hand all cell membranes, modulating their - of soft fluidity. In specialized tissues, cholesterol is a & precursor of bile acids, steroid hormones, and vitamin D.  - 51 - & S & & / - ⑮ our - O ② ↓ses * & influx & 29 * - & Sources of liver & cholesterol (influx) and f routes by which cholesterol leaves the liver O (efflux) effect tis livee func & Sue & ~ He tim & - ↑ & &  Sources of liver cholesterol (influx) and routes by which cholesterol leaves the liver (efflux) O The liver plays a central role in the regulation of the body's cholesterol dietarye comins homeostasis. O Sources of hepatic cholesterol: by denovo S andPhepatic dietary cholesterol (From lings tissue chylomicron remnants) cholesterol synthesized de novo by extrahepatic tissues and by the liver itself. Sources of liver cholesterol (influx) and routes by which cholesterol leaves the liver (efflux) O Cholesterol is eliminated from the liver as : free unmodified cholesterol in the bile, or it can be converted to bile salts that are secreted into the intestinal - lumen. - It can also serve as a component of plasma lipoproteins sent to the peripheral tissues.  Structure of Cholesterol O Cholesterol is a very 8 C branched from z I hydrophobic compound. the 2-17 of Dring · 2 ⑧F17 · 7 O It consists of four fused & & hydrocarbon rings (A, B, C, & and D, called the “steroid nucleus”), and it has an eight-carbon, branched hydrocarbon chain attached to C-17 of the D ring.  Structure of Cholesterol O Ring A has a hydroxyl group at C-3, and ring B has a double bond between C-5 and C-6. 0 Se I =  Synthesis of 3-hydroxy-3- methylglutaryl (HMG) CoA & O First, two acetyl * CoA molecules condense to form & sta acetoacetyl CoA. sof --- 3 O Next, a third & & Acty/ molecule of acetyl & Of &; - > CoA is added, Not I x]/ - Vate producing HMG CoA, a six-carbon Step niting Sax compound.  Synthesis of mevalonic acid (mevalonate) · O The next step, the & & reduction of HMG CoA to mevalonic acid, is catalyzed by HMG CoA reductase, and is the ⑧ rate-limiting and key regulated step in cholesterol synthesis.  Synthesis of mevalonic acid (mevalonate) O It occurs in the cytosol, uses two molecules of NADPH as the reducing agent, and releases CoA, making the reaction irreversible.  Phosphorlation 6-C Synthesis of cholesterol from & mevalonic acid. ⑤ a S & & & 1 - & & Pyra N- Pos &I = & && & & moleume & - molecule & I · -& 251. saturation & S & = 302 &  Synthesis of cholesterol from mevalonic acid 1. Mevalonic acid is converted to 5- pyrophosphomevalonate in two steps, each of which transfers a phosphate group from ATP. 2. A five-carbon isoprene unit—isopentenyl pyrophosphate (IPP)—is formed by the decarboxylation of 5- pyrophosphomevalonate. The reaction requires ATP.  3. IPP is isomerized to 3,3-dimethylallyl pyrophosphate (DPP). 4. IPP and DPP condense to form ten-carbon geranyl pyrophosphate (GPP). - Endense 5. A second molecule of IPP then condenses with GPP to form 15-carbon farnesyl pyrophosphate (FPP). o iden  6. Two molecules of FPP combine, releasing pyrophosphate, and are reduced, forming the 30-carbon compound squalene. E OCombain releasing C  7. Squalene is converted to the sterol lanosterol by a sequence of reactions that use molecular oxygen and NADPH. The hydroxylation of squalene triggers the & cyclization of the structure to lanosterol. & The conversion of lanosterol to cholesterol is a multistep 8. > - remove methyl process, group 2 resulting in the shortening of the carbon chain 2 - 4 > - migrate double bond from 30 to 27 carbons, removal of the 2 methyl groups 2 at C-4, migration of the double bond from C-8 to C-5, and C - = c - 5 > - reduction double band 2- 24 , reduction of the double bond between C-24 and C-25. 2026  Regulation of cholesterol synthesis O HMG CoA reductase, the rate-limiting enzyme, is the major control point for cholesterol biosynthesis, and is subject to different kinds of metabolic control.  ↑ 1.Sterol-dependent regulation of gene expression O Expression of the HMG CoA reductase gene is controlled by the transcription factor, SREBP (sterol regulatory element–binding protein) that binds DNA at the cis-acting sterol regulatory element (SRE) of the reductase gene. S = ne[ I · ! - Sterol-dependent regulation of gene expression O SREBP is an integral protein of the ER membrane, and associates with a second ER membrane protein, SCAP (SREBP cleavage–activating protein). gens = 2 = trans C facription & O & Y complex & ER Se 3 A S · -- 4  Regulation of HMG CoA reductase gene O When sterol levels in the cell are low, the SREBP-SCAP complex is sent out of the ER to the Golgi.  Regulation of HMG CoA reductase gene O In the Golgi, SREBP is acted upon by proteases which generate a soluble fragment that enters the nucleus and functions as a transcription factor. ↳ h  Regulation of HMG CoA reductase gene O This results in increased synthesis of HMG CoA reductase and, therefore, increased cholesterol synthesis.  Regulation of HMG CoA reductase gene O If sterols are abundant, however, they induce the binding of SCAP to yet other ER membrane proteins. ER D j nigh S - - 2 - 24 - on - 0 Komal C & - N  Regulation of HMG CoA reductase gene O This results in the retention of the SCAP-SREBP in the ER, thus preventing the activation of SREBP, and leading to down-regulation of cholesterol synthesis.  T · C 6 ↳ O 52. ② & 2. Sterol-accelerated enzyme degradation O The reductase itself is an integral protein of the ER membrane. When sterol levels in the cell are high, the reductase binds to proteins. O This binding leads to ubiquitination 3 and proteasomal degradation of the reductase. lay zzying &  &/I - 3. Sterol-independent phosphorylation/dephosphorylation O HMG CoA reductase activity is controlled covalently through the phosphoria in actions of adenosine is monophosphate (AMP)–activated C protein kinase (AMPK) and a & acting ②phosphoprotein phosphatase. & & & b S acting s lacting inactive C  Sterol-independent phosphorylation/dephosphorylation O The phosphorylated form of the enzyme is inactive, whereas the dephosphorylated form is active.  4. Hormonal regulation O The amount (and, therefore, the activity) of HMG CoA reductase is controlled hormonally. O An increase in insulin favors S up- · &regulation of the expression of the HMG CoA reductase gene. & g O Glucagon has the opposite effect. En , Keton is :9. &. 8 2 , give & is S Glucagon stimulates phosphorylation (inactivation), and insulin bodies promotes dephosphorylation, activating the enzyme and favoring cholesterol synthesis..  5. Inhibition by drugs O The statin drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) are structural analogs of HMG - CoA, and are (or are metabolized to) & S reversible, competitive inhibitors of HMG ubstrate H CoA reductase. men Os · O They are used to decrease plasma - & cholesterol levels in patients with · Ea hypercholesterolemia o Structural similarity of HMG and simvastatin Y  bile acid-- & Degradation of Cholesterol free S Cholestrel O The ring structure of cholesterol cannot be metabolized to CO2 and H2O in humans. O Rather, the intact sterol nucleus is eliminated from the body by : conversion to bile acids and bile salts, which are excreted in the feces, secretion of cholesterol into the bile, which transports it to the intestine for elimination. Degradation of Cholesterol O Some of the cholesterol in the intestine is modified by bacteria before excretion. O The primary compounds made are the isomers coprostanol - and cholestanol, S E = & e which are reduced derivatives of - cholesterol. Together with cholesterol, these compounds make up the bulk of & neutral fecal sterols.  Products derived from chloresterol: Steroid Hormones O Cholesterol is the precursor of all classes of steroid hormones: glucocorticoids (for example, cortisol), mineralocorticoids (for example, aldosterone), and sex hormones— androgens, estrogens, and progestins.  && 1 & s Key steroid hormones thank you