br The sources of cholesterol secreted
The sources of cholesterol secreted into bile Bile formation is an osmotic process and solutes are actively transported into the canaliculus by primary active lipid transporters: ABCG5/G8 for biliary cholesterol secretion, ABCB4 for biliary phospholipid secretion, and ABCB11 for biliary bile acid secretion. The most important solutes driving bile formation are bile acids. Three important physiological functions of bile formation are: (i) it is a major route for the elimination of cholesterol from the body, either as unesterified cholesterol or as bile acids, the end productions of cholesterol degradation; (ii) it ensures the secretion of bile acids, which are crucial for lipid emulsification in the small intestinal tract and subsequent lipid alk inhibitor by the enterocytes; and (iii) it represents an important pathway for the removal of drugs, toxins, and waste productions from the body. As shown in Fig. 3, the metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver. Input is dependent on the amount of both unesterified and esterified cholesterol taken up by the liver from plasma lipoproteins (LDL > HDL > chylomicron remnants) plus hepatic de novo biosynthesis. Output is dependent upon the amount of cholesterol disposed within the liver after its conversion to cholesteryl esters (to form new VLDL plus ester storage) minus the amount of cholesterol converted to the primary bile acids, such as cholic acid and chenodeoxycholic acid. Overall, the liver can systematically regulate the total amount of cholesterol within it, and any excess cholesterol can be handled efficiently. When no dietary cholesterol is consumed, bile contains newly synthesized cholesterol from the liver as well as preformed cholesterol, which reach the liver via several different ways. Under the circumstances, it is estimated that ∼85% of total biliary cholesterol is derived from the pools of preformed cholesterol within the liver and less than 15% of the cholesterol in bile comes from hepatic de novo biosynthesis. The sources of preformed cholesterol are derived from hepatic uptake of plasma lipoproteins, such as HDL, LDL, and VLDL through their respective receptors on the basolateral membrane of hepatocytes. Consistent with its predominant physiological function in reverse cholesterol transport, HDL transfers cholesterol from the extrahepatic tissues to the liver for biliary secretion, which is the major lipoprotein source of cholesterol that is targeted for hepatic secretion into bile. Acetyl-CoA is often used as a substrate for the hepatic de novo biosynthesis of cholesterol, which is regulated mainly by 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in this cholesterol synthesis pathway in the liver. This enzyme is up- or down-regulated depending on the overall cholesterol balance in the liver. Increasing its enzymatic activity could enhance hepatic secretion of biliary cholesterol. However, its inhibition by statins reduces hepatic cholesterol secretion by less than 10%. Most, but not all, studies showed that the use of oral contraceptive steroids and conjugated estrogens in premenopausal women significantly increases the incidence of cholesterol gallstones. The administration of estrogen to postmenopausal women and estrogen therapy to men with prostatic carcinoma display similar lithogenic effects, leading to hepatic cholesterol hypersecretion and biliary lithogenicity. Animal studies found that hepatic estrogen receptor α (ERα) activated by estrogen interferes with the negative feedback regulation of cholesterol biosynthesis by stimulating sterol-regulatory element binding protein-2 (SREBP-2), which activates the SREBP-2 responsive genes for the cholesterol biosynthetic pathway. Thus, under conditions of high levels of estrogen, mice continue to synthesize cholesterol in the face of its excess availability from the high-cholesterol diet, suggesting that there is a loss in the negative feedback regulation of cholesterol biosynthesis that results in excess secretion of newly synthesized cholesterol and supersaturation of bile. These abnormalities lead to a predisposition to cholesterol gallstone formation. These findings highlight the importance of estrogen in the pathogenesis of gallstones because more newly synthesized cholesterol determined by the estrogen-ERα-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion and the formation of supersaturated bile.