Health & Medical hepatitis

Molecular Alterations in Hepatocyte Transport Mechanisms

´╗┐Molecular Alterations in Hepatocyte Transport Mechanisms
Recent advances in the molecular cloning of membrane transport systems that determine bile formation have facilitated studies of the molecular mechanisms of cholestatic liver disease. The present review summarizes what has been learned about the molecular alterations of these membrane transporters in hepatocytes and cholangiocytes in acquired cholestatic liver disorders. Much of this information has been obtained from the study of animal models of cholestasis and from more limited studies in clinical cholestatic liver diseases. Many of these responses may be interpreted as adaptations that serve to diminish cholestatic liver injury.

Impairment of hepatic transport mechanisms for bile salts and numerous other organic solutes are prominent features of both inherited and acquired forms of cholestatic liver injury. The recent cloning and functional characterization of a number of these hepatocyte-specific transporters has helped define the molecular mechanisms involved in bile formation and has advanced our understanding of both genetic and acquired cholestatic disorders. Mutations have been identified in genes corresponding to a number of these transport proteins in patients with previously defined inherited clinical phenotypes, including Dubin-Johnson syndrome and several forms of progressive familial intrahepatic cholestasis (PFIC). These discoveries have provided convincing proof that these transporters are critical determinants of bile secretory function. In this review, we address the defects in hepatic transporters that occur in acquired forms of liver injury, many of which share clinical, biochemical, and histologic features with the less common inherited forms of liver injury.

Acquired forms of cholestatic liver injury include disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis secondary to sepsis, drug-induced cholestasis, and cholestasis of pregnancy. They are responsible for, among others, the major clinical burden compared with inherited conditions such as errors in bile acid metabolism or PFICs. Therefore, an understanding of the molecular and pathophysiologic mechanisms that result in these cholestatic syndromes is an important goal toward effective clinical management. Thus, the aim of this chapter is to review our current understanding of the alterations in hepatocyte transport systems that occur in various forms of acquired cholestatic liver injury. Much of this information has resulted from evaluations of the molecular expression and function of the major cloned hepatic transporters that determine bile production using several cholestatic animal models of liver injury. In addition, several other in vitro studies and more limited studies in human cholestatic disorders have also contributed to this information.

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