Intestinal cholesterol biosynthesis

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Arjmandi, B. H., Craig, J., Nathani, S., and Reeves, R. D. (1992). Soluble dietary fiber and cholesterol influence in vivo hepatic and intestinal cholesterol biosynthesis in rats. /. Nutr. 122,1559-1565. 

The material (H) has been tested with preparations of rat liver hepatocytes and has been found to enter them and to serve as an inhibitor of cholesterol biosynthesis therein. Using (H) bearing a specific radiocarbon label, studies have been performed in intact animals. The material has been injected IV and found to be cleared from the blood rapidly, the major portion being delivered to the liver. Small portions are found in bile and intestine, but not in other organs of the animals. 

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. 

Inhibition of cholesterol biosynthesis occurred in the small intestine of rats after administration of D-limonene for 7 days, but no significant effect on the secretion of radiolabeled cholesterol into bile and feces was observed. o-Limonene increased the perfusion pressure of the sphincter of Oddi in dogs when injected IV or directly into the common bile duct. 

The major site of steroid synthesis in animals has been considered to be the liver, but recently (1975) this has been disputed and detailed studies now show that sterol synthesis in guinea pig occurs more readily in ileum and lung than in liver under a variety of conditions" " and a brief study indicates similar sites of biosynthesis in swine." All tissues of guinea pig studied had an active feedback system controlling cholesterol biosynthesis and the results of feeding cholesterol and cholestyramine" showed that both the former and possibly bile acids suppress cholesterol synthesis in the liver to a far lesser extent than in the small intestine. 

The mode of action of clofibrate has yet to be completely elucidated. Sterol balance data in man supported the widely accepted concept that the drug inhibits cholesterol biosynthesis. However, in rats fed 0.25% clofibrate for 2 weeks, no inhibition in the absolute rates of cholesterol biosynthesis was observed in liver, intestinal wall or adipose tissue ([ H]20 incorporation to cholesterol). Intralipid clearance from the plasma of rats and hyperlipidemic patients was enhanced by cloflbrate, demonstrating Increased fractional turnover rate of endogenous triglyceride. Clofibrate enhanced the activity of post-heparin plasma lipo-... 

Cholesterol can be obtained from the diet or it can be synthesized de novo. An adult on a low-cholesterol diet typically synthesizes about 800 mg of cholesterol per day. The liver is the major site of cholesterol synthesis in mammals, although the intestine also forms significant amounts. The rale of cholesterol formation by these organs is highly responsive to the cellular level of cholesterol. This feedback regulation is mediated primarily by changes in the amount and activity of 3-hydroxy 3 methylglutaryl CoA reductase. As described earlier (p. 739), this enzyme catalyzes the formation of meval-onate, the committed step in cholesterol biosynthesis. HMG CoA reductase is controlled in multiple ways ... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants stimulates expression of the hepatic genes regnlating LDL-receptor expression and cholesterol biosynthesis. The greater expression of hepatic LDL receptors enhances LDL-C clearance from the plasma. 

The actions of ezetimibe are complementary to those of statins. Statins, which inhibit cholesterol biosynthesis, increase intestinal cholesterol absorption. Ezetimibe, which inhibits intestinal cholesterol absorption, enhances cholesterol biosynthesis by as much as 3.5 times in experimental animals. Dual therapy with these two classes of drugs prevents the enhanced cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorption induced by statins. This combination provides additive reductions in LDL-C levels irrespective of the statin employed. There is a further reduction of 15 to 20% in LDL-C when ezetimibe is combined with any statin at any dose. Increasing statin dosages from the usual starting dose of 20 mg to 80 mg normally yields only an additional 12% reduction in LDL-C, whereas adding ezetimibe, 10 mg daily, to 20 mg of a statin will reduce LDL-C by an additional 18 to 20%. 

Cholesterol travels in the bloodstream via lipoprotein complexes called Chylomicrons, VLDL, IDL, LDL, and HDL. Of the five lipoprotein classes, LDL is by far the richest in cholesterol. Cholesterol in plasma lipoproteins exists both as the free sterol and esterified at its hydroxyl position with a long-chain fatty acid, usually unsaturated (see also Table 18.1). The LDL particle contains a single molecule of apoprotein B-lOO (Mr = 513,000) as its primary protein component. Because cholesterol biosynthesis is confined primarily to the liver with some occurring also in intestine, LDL plays an important role in delivering cholesterol to other tissues. Cholesterol esters are too hydrophobic to traverse cell membranes by themselves and must be transported into cells via specialized LDL receptors. 

In addition to the liver and intestine (where cholesterol upon incorporation as lipoproteins reaches blood circulation), cholesterol biosynthesis occurs in almost all tissues. The rates of cholesterol synthesis may be high in organs or tissues, such as liver, developing brain, skin (epidermis), adrenal glands, and malignant tumors, or it may be low as in mature brain, kidney. 

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