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New insights into the role of lith genes in the formation of cholesterol-supersaturated bile

Liver Research 2017年第1期1卷 42-53页

作者： Helen H.Wang Tiangang Li Piero Portincasa David A.Ford Brent A.Neuschwander-Tetri Patrick Tso David Q-H.Wang Department of Internal Medicine Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt.LouisMOUSA Department of Pharmacology Toxicology and TherapeuticsKansas University Medical CenterKansas CityKSUSA Clinica Medica“A.Murri” Department of Biomedical Sciences and Human OncologyUniversity of Bari“Aldo Moro”Medical SchoolBariItaly Department of Biochemistry and Molecular Biology Saint Louis University School of MedicineSt.LouisMOUSA Department of Pathology and Laboratory Medicine University of Cincinnati College of MedicineCincinnatiOHUSA

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed.lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones.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.The sources of cholesterol for hepatic secretion into bile have been extensively investigated;however,to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state.Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion,the genetic mechanisms that cause supersaturated bile have not been defined yet.Identification of the lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation.In this review article,we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology.A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel,effective,and noninvasive therapies for patients with gallstones,which would reduce the morbidity,mortality,and costs of health care associated with gallstones,a very prevalent liver disease worldwide.

关键词： Bile flow Bile acid Biliary secretion lith gene Micelle Vesicle

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