New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile.
New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile.
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DOI：
10.1016/j.livres.2017.05.005
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Wang DQ
中科院分区：
文献类型：
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作者：
Wang HH;Li T;Portincasa P;Ford DA;Neuschwander-Tetri BA;Tso P;Wang DQ
胆固醇结石的形成代表胆汁胆固醇稳态的失败，其中胆固醇在胆汁中溶解度的物理化学平衡被扰乱。致石性胆汁主要是由胆汁胆固醇的持续性肝脏分泌过多引起的，持续的胆固醇过饱和胆汁是胆固醇固体一水合物晶体沉淀和胆固醇结石形成的必要先决条件。胆汁分泌所需的肝胆固醇分子供应的代谢决定因素取决于肝脏中胆固醇及其代谢产物的输入-输出平衡。肝分泌到胆汁中的胆固醇来源已被广泛研究;然而，在正常生理条件下和成石状态下，每种胆固醇来源对肝分泌的贡献程度仍不清楚。虽然人们早就知道胆汁成石是由肝脏胆固醇分泌过多引起的，但引起胆汁过饱和的遗传机制尚未确定。确定Lith基因，决定肝胆固醇分泌过多，应提供新的见解的主要遗传和病理生理缺陷的胆结石形成。本文主要从遗传学和病理生理学的角度对过饱和胆汁和胆结石的发病机制进行综述。更好地了解胆固醇过饱和胆汁形成的分子遗传学和病理生理学，无疑将促进胆结石患者新型、有效和非侵入性治疗的发展，这将降低胆结石（一种全球非常普遍的肝病）相关的发病率、死亡率和医疗费用。
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.