Cholesterol Endogenous

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

Rosuvastatin calcium (56 Crestor ) Mevastatin Statin NP-derived Microbial Dyslipidemia Inhibits ttie rate-limiting step in hie formation of endogenous cholesterol by HMG-CoA reductase 215-217, 492-495... 

Cholesterol can be derived from two sources—food or endogenous synthesis from ace-tyl-CoA. A substantial percentage of endogenous cholesterol synthesis takes place in the liver. Some cholesterol is required for the synthesis of bile acids (see p. 314). In addition, it serves as a building block for cell membranes (see p. 216), or can be esterified with fatty acids and stored in lipid droplets. The rest is released together into the blood in the form of lipoprotein complexes (VLDLs) and supplies other tissues. The liver also contributes to the cholesterol metabolism by taking up from the blood and breaking down lipoproteins that contain cholesterol and cholesterol esters (HDLs, IDLs, LDLs see p.278). 

Decreased levels of internalized cholesterol lead to elevated activity of the chief enzyme responsible for endogenous cholesterol synthesis, HMG-CoA reductase, and consequent excessive synthesis of cholesterol. 

Squalene takes part in metabolism as precursor for synthesis of steroids and structurally quite similar to (3-carotene, coenzyme qlO, vitamins Ki, E, and D. The squalene in skin and fat tissue comes from endogenous cholesterol synthesis as well as dietary resources in people who consume high amounts of olive and fish oil especially shark liver (Gershbein and Singh, 1969). Squalene is synthesized by squalene synthase which converts two units of farnesyl pyrophosphate, direct precursor for terpenes and steroids, into squalene. As a secosteroid, vitamin D biosynthesis is also regulated by squalene. Moreover, being precursor for each steroid family makes squalene a crucial component of the body. 

Schneider, C.L., Cowles, R.L., Stuefer-Powell, C.L., and Carr, T.P. 2000. Dietary stearic acid reduces cholesterol absorption and increases endogenous cholesterol excretion in hamsters fed cereal-based diets. J. Nutr. 130, 1232-1238. 

In this light, cholesterol absorption has received intense focus for several decades. Although the various statins lower LDL by decreasing endogenous cholesterol synthesis, another approach to prevent excess cholesterol accumulation is to reduce absorption of dietary cholesterol. Doing so also prevents reabsorption of biliary cholesterol, which can have a major impact on overall cholesterol metabolism since recirculation of biliary cholesterol represents a large portion of the cholesterol that transits through the intestine. For recent reviews on mechanisms of cholesterol and lipid absorption, see ref. (1-3). 

High density lipoproteins (HDLs) transport endogenous cholesterol from the tissues to the liver. 

Bile acid sequestrates are anion-exchange resins, which sequester bile acid in the intestine. Cholestyramine and colestipol are the most commonly used in this category, which by this mechanism prevents bile acid re-absorption and causes decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acid in the liver by preventing enterohepatic recirculation. This leads to an increased expression of LDL receptors in liver and causes increased removal of LDL from blood and reduces the LDL cholesterol in the plasma. 

Both IDL and LDL can be removed from the circulation by the liver, which contains receptors for ApoE (IDL) and ApoB-100 (IDL and LDL). After IDL or LDL interacts with these receptors, they are internalized by the process of receptor-mediated endocytosis. Receptors for ApoB-100 are also present in peripheral tissues, so that clearance of LDL occurs one-half by the liver and one-half by other tissues. In the liver or other cells, LDL is degraded to cholesterol esters and its other component parts. Cholesterol esters are hydrolyzed by an acid lipase and may be used for cellular needs, such as the building of plasma membranes or bile salt synthesis, or they may be stored as such. Esterification of intracellular cholesterol by fatty acids is carried out by acyl-CoA-cholesterol acyltransferase (ACAT). Free cholesterol derived from LDL inhibits the biosynthesis of endogenous cholesterol. B-100 receptors are regulated by endogenous cholesterol levels. The higher the latter, the fewer ApoB-100 receptors are on the cell surface, and the less LDL uptake by cells takes place. 

It is clear from Equation (19.4) that saturated fat, not cholesterol, is the single most important factor that raises serum cholesterol. Some cases of hyperlipoproteinemia type IV (high VLDL) respond to low-carbohydrate diets, because the excess of VLDL comes from intestinal cells, where it is produced from dietary carbohydrate. Resins, such as cholestyramine and cholestipol, bind and cause the excretion of bile salts, forcing the organism to use more cholesterol. Lovastatin decreases endogenous cholesterol biosynthesis (see later), and niacin (nicotinic acid) apparently decreases the production of VLDL and, consequently, LDL. It also results in an HDL increase. Antioxidants that inhibit the conversion of LDL to oxidized LDL have also been used with some success. These are high doses of vitamin E and the drug probucol. 

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing their re-absorption. In so doing, more endogenous cholesterol is directed to the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are excreted in the faeces. 

Intermediate-density lipoprotein Endogenous cholesterol esters (IDL)... 

High-density lipoprotein (HDL) Endogenous cholesterol esters... 

Ergocalciferol is derived from ergosterol in the diet. Colecalciferol is derived from endogenous cholesterol. Both are also synthesized in the skin. Colecalciferol and ergocalciferol are converted in the liver by hydroxylation to calcifediol, which is weakly active. Calcifediol is activated in the kidneys by further hydroxylation to alfacalcidol, which is highly active, and calcitriol, which is weakly active. Calcitriol is deactivated by further hydroxylation in the kidney to 1 a,24,25-trihydroxycolecalcif erol. 

The hypocholesterolemic eflFect of L-ascorbic acid is most prevalent in humans with low levels of tissue ascorbate and in whom hypercholesterolemia results from a chronic imbalance between an enhanced input of exogenous or endogenous cholesterol and a reduced output in the form of bile acids. The most striking hypocholesterolemic eflFect of ascorbate has been observed in elderly hypercholesterolemic humans... 

Shefer, S., Gheng, F. W., Hauser, S., Batta, A. K., and Salen, G., Regulation ofbile acid synthesis. Measurement of cholesterol 7 -hydroxylase activity in rat liver microsomal preparations in the absence of endogenous cholesterol. J. Lipid Res. 22, 532-536... 

Gustafsson has reported that Ca " and Mg " have different effects on mitochondrial 26-hydroxylation of endogenous cholesterol, exogenous cholesterol and 5j8-cholestane-3o,7a,12a-triol [132]. He concluded that there might be different transport mechanisms for the two substrates through the mitochondrial membranes. This was later supported by studies by Pedersen et al., showing that the stimulatory effect of Mg was similar for hydroxylation of several substrates catalysed by a partially purified system [133]. 

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