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    • 5ht receptors Under conditions of high cholesterol consumpti

    2019-05-21

    Under conditions of high cholesterol consumption, an appreciable fraction of cholesterol in bile is derived from the diet through the chylomicron pathway to the liver. Dietary cholesterol reaches the liver through the intestinal lymphatic routes as of chylomicrons, and subsequently, chylomicron remnants after chylomicrons are hydrolyzed by plasma lipoprotein lipase and hepatic lipase. Under the circumstances, newly synthesized cholesterol in the liver is reduced, which consists of only approximately 5% of biliary total cholesterol. The small intestine is a unique organ providing dietary and re-absorbed biliary cholesterol to the body. Clinical studies and epidemiological investigations have found that cholesterol cholelithiasis is prevalent in cultures consuming a “Western” diet that consists of high total calories, cholesterol, saturated fatty acids, refined carbohydrates, proteins, and salt, as well as low fiber. In addition, its incidence in North and South America, as well as in European countries, is significantly higher than that in Asian and African populations. Several clinical studies have found an association between the increased incidence of cholesterol gallstones in China and a “westernization” of the traditional Chinese diet. Cholesterol cholelithiasis once was rare in Japan, but the incidence is now increased markedly mostly because of over the past half a century with the adoption of Western-type dietary habits. Because biliary cholesterol hypersecretion is an important prerequisite for cholesterol gallstone formation, biliary cholesterol secretion and saturation could be significantly reduced by inhibiting cholesterol 5ht receptors and hepatic uptake of chylomicron remnants. More importantly, there is a significant and positive correlation between the efficiency of intestinal cholesterol absorption and the prevalence of cholesterol gallstone formation in 15 strains of inbred mice, implying that high efficiency of intestinal cholesterol absorption and high dietary cholesterol are two independent risk factors for cholesterol gallstone formation.A new finding showed that the potent cholesterol absorption inhibitor ezetimibe prevents the formation of cholesterol gallstones, and facilitates the dissolution of gallstones by forming an abundance of unsaturated micelles in gallstone-susceptible C57 L/J mice carrying Lith1 and Lith2 genes. In addition, ezetimibe significantly reduces biliary cholesterol saturation and retards cholesterol crystallization in the bile of patients with gallstones, suggesting that it may act as a potent biliary cholesterol-desaturating agent in patients with gallstones. These findings indicate that ezetimibe is a novel approach to reducing biliary cholesterol content and provides a promising strategy for preventing or treating cholesterol gallstones by inhibiting intestinal cholesterol absorption.
    Disruption of hepatic lipid secretion leading to the formation of cholesterol-supersaturated bile Because bile is an aqueous solution and cholesterol is virtually insoluble in water, the mechanisms for cholesterol solubilization in bile are complex. Clinical studies and animal investigations have found that hepatic hypersecretion of biliary cholesterol is the primary defect in the pathogenesis of cholesterol gallstone disease. Hepatic cholesterol hypersecretion into bile may or may not be accompanied by normal, high, or low hepatic secretion rates of biliary bile acids and phospholipids. Cholesterol-supersaturated bile is often defined as a state in which cholesterol cannot be solubilized in bile by biliary bile acids and phospholipids at equilibrium. Therefore, the formation of supersaturated bile is often caused by (i) hepatic hypersecretion of biliary cholesterol; (ii) reduced hepatic bile acid and phospholipid secretion with normal biliary cholesterol secretion; or (iii) a combination of hepatic cholesterol hypersecretion with hyposecretion of these solubilizing lipids. Many animal studies have provided direct evidence showing that bile acids stimulate secretion of vesicles by the hepatocytes, and these unilamellar vesicles are always detected in freshly collected hepatic bile. Accumulated evidence from the genetic study of sitosterolemia has shown that the efflux of biliary cholesterol from the canalicular membrane could be a protein-mediated process. This led to the discovery of ABCG5/G8, which plays a critical role in the cellular efflux of cholesterol, and its significance for bile formation has been examined in genetically modified mice. Overexpression of ABCG5/G8 in the liver increases the cholesterol content of gallbladder bile. In contrast, the hepatic secretion rate of biliary cholesterol is reduced in Abcg5/g8 double knockout mice and in Abcg5 or Abcg8 knockout mice. In addition, scavenger receptor class B type I (SR-BI), the HDL receptor, is localized mainly in the sinusoidal, and perhaps, in the canalicular membrane of hepatocytes. In transgenic and knockout mice, biliary secretion of cholesterol varies in proportion to the hepatic expression of SR-BI, and the established contribution of SR-BI to the sinusoidal uptake of HDL cholesterol is destined for secretion into bile.