Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation

Abstract

Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.

Figure 1

(a) Possible molecular mechanisms of action of nuclear receptors at the liver and the small intestine. Cholesterol derived from the diet as well as from the bile enters the intestine and is absorbed by the enterocytes through NPC1L1 and can be secreted back to the intestinal lumen by ABCG5/G8. After absorption, cholesterol is incorporated into lipoproteins (Lps), secreted into lymph and blood, and transported to the liver after triglyceride uptake in peripheral tissues. Bile salts (BSs) are absorbed in the intestine by the ASBT transporter and exit into the basolateral surface through OSTα/β transporters, among others, reaching the liver via the systemic blood circulation. The hepatic pool of cholesterol originates from de novo synthesis from acetyl-CoA as well as receptor-mediated endocytosis and/or selective lipid uptake from Lp. Cholesterol can be secreted into plasma HDL through ABCA1 transporter or by formation and secretion of VLDL (not shown) or into the bile through the heterodimeric ABCG5/8 transporter. Bile is constituted by cholesterol (CH), phospholipids (PLs), and BSs. PL enters the biliary canaliculi through the ABCB4 transporter. BSs, obtained by neosynthesis from cholesterol or by uptake from plasma, are secreted into the bile by the ABCB11 transporter. The NRs control metabolism and secretion of lipids at different levels: LXR promotes cholesterol efflux from the intestine and from the liver by activation of ABG5/8 and ABCA1 transporters. Also, LXR activates Cyp7A1 leading to an increase in BS synthesis in the liver. The FXR receptor regulates BS concentration at two different levels: promoting the expression of FGF15/19, ILBP, and OSTα/β transporters in the intestine as well as increasing the expression of ABCB4 and ABC11 transporters and repressing Cyp7A1 expression in the liver. ESRs increase de novo cholesterol synthesis by regulation of HMGCoAR.ASBT: apical sodium bile acid transporter. OSTα/β: organic solute transporter alpha/beta (b) Cholesterol gallstone formation. An increase in cholesterol and/or a decrease in BS or PL contents in the bile lead to an increase in the biliary cholesterol saturation index (CSI) triggering cholesterol precipitation into crystals and ultimately the formation of cholesterol stones within the gallbladder.