Therapeutic Reflections in Cholesterol Homeostasis and Gallstone Disease: A Review

Agostino   Di   Ciaula; David   Q.-H.   Wang; Gabriella      Garruti; Helen   H.   Wang; Ignazio      Grattagliano; Ornella   de   Bari; Piero      Portincasa

Abstract

Cholesterol gallstone disease is one of the most prevalent and the most costly digestive diseases in Western countries. Its pathogenesis is a complex paradigm resulting from the interaction of genetic factors, hepatic hypersecretion of cholesterol, increased intestinal absorption of cholesterol, a constantly “supersaturated” bile, crystallization of biliary cholesterol, and gallbladder stasis. De novo cholesterol biosynthesis, biliary cholesterol output, and intestinal cholesterol absorption are therefore key steps involved in cholesterol homeostasis. Establishing the right pharmacological therapy for cholesterol gallstones is of major importance in Western healthcare systems. Certain drugs might independently influence cholesterol gallstone formation by blocking the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibiting cholesterol biosynthesis in the liver (statins) or blocking cholesterol absorption in the small intestine apical membrane by specifically inhibiting the Niemann-Pick C1-like 1 protein (ezetimibe). This review will focus on the possibility that statins and ezetimibe, by acting at different levels of cholesterol homeostasis, might represent novel therapeutic approaches to prevent cholesterol gallstones in selected subjects at risk.

Keywords: Cholelithiasis, cholesterol synthesis, cholesterol absorption, enterohepatic circulation, metabolic syndrome, Niemann- Pick C1-like 1, obesity.