Bile acid homeostasis an Introduction

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Bile acids are end products of cholesterol catabolism. Bile acid synthesis generates bile flow from the liver to the intestinal tract and back to the liver. This process of enterohepatic circulation of bile is extremely efficient and plays important roles in liver function, metabolic regulation, and liver physiology. Bile acids are amphipathic molecules that function as powerful detergents to facilitate absorption of lipids and nutrients and excretion of cholesterol and toxic metabolites. When accumulated in high concentrations, hydrophobic bile acids damage cell membranes, impair liver function, and cause cholestasis and cirrhosis. The liver plays a central role in maintaining cholesterol homeostasis by balancing de novo cholesterol and bile acid synthesis, dietary cholesterol uptake, biliary cholesterol excretion, lipoprotein synthesis and secretion, and reverse cholesterol transport from peripheral tissues to the liver for catabolism to bile acids (Fig. 51).

fig to be added 1 june 2011 noragon

However, molecular mechanisms underlying this complex metabolic regulation are not completely understood. Cloning of the genes encoding cholesterol 7 -hydroxylase (cytochrome P-450 7A1; CYP7A1) and other key regulatory enzymes in the bile acid biosynthetic pathway has provided molecular tools for elucidation of regulatory mechanisms. Discovery of human mutations in bile acid biosynthetic genes in patients with liver and cardiovascular diseases has provided evidence that bile acid synthesis is linked to cholesterol metabolism and that a deficiency of bile acid synthesis leads to dyslipidemia, liver cirrhosis, gallstone disease, and cardiovascular diseases in humans. Recent studies have uncovered that bile acids are ligands of several nuclear hormone receptors involved in regulating bile acid synthesis, transport, and cholesterol metabolism. These recent developments have generated great interest in bile acid research and will lead to the early diagnosis of diseases and discovery of new therapeutic strategies for treating human disorders in bile acid and cholesterol metabolisms. This review will summarize the roles of bile acids and nuclear receptors in regulation of bile acid and cholesterol homeostasis.

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