Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids

Abstract

Cholesterol crystal formation in the gallbladder is a key step in gallstone pathogenesis. Gallbladder epithelial cells might prevent luminal gallstone formation through a poorly understood cholesterol absorption process. Genetic studies in mice have highlighted potential gallstone susceptibility alleles, Lith genes, which include the gene for megalin. Megalin, in conjunction with the large peripheral membrane protein cubilin, mediates the endocytosis of numerous ligands, including HDL/apolipoprotein A-I (apoA-I). Although the bile contains apoA-I and several cholesterol-binding megalin ligands, the expression of megalin and cubilin in the gallbladder has not been investigated. Here, we show that both proteins are expressed by human and mouse gallbladder epithelia. In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression. The effects of bile acids (BAs) were also demonstrated in vivo, analyzing gallbladder levels of megalin and cubilin from mice fed with different BAs. The BA effects could be mediated by the farnesoid X receptor, expressed in the gallbladder. Megalin protein was also strongly increased after feeding a lithogenic diet. These results indicate a physiological role for megalin and cubilin in the gallbladder and provide support for a role for megalin in gallstone pathogenesis.

Biliary lipids and cholesterol gallstone disease

“…22. cholesterol molecules (28) and their incorporation into and stiffening of sarcolemmal membranes (29). The result is diversion of more hepatic bile into the intestine and as a consequence elevation in deoxycholate conjugate levels in bile (15).…”

The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation

“…Both transporters are upregulated in gallbladders from patients with cholesterol gallstone disease [6]. Thus far, on the apical side the expression of ACBG5/G8 [7], scavenger receptor class B type I (SR-BI) [8], cubilin and megalin [9] was reported in gallbladder epithelial cells. The obligate heterodimer ABCG5/G8 is a cholesterol transporter expressed in enterocytes and hepatocytes, where it mediates the excretion of cholesterol and plant sterols out of the cell [1].…”

Cholesterol gallstone disease: focusing on the role of gallbladder

“…72 Furthermore, ABCA1, ABCG5/G8, and megalin, but not cubilin, are more highly expressed at protein levels in gallbladders with cholesterol gallstones than in normal gallbladders. 73,78 In contrast, increasing the bile cholesterol content with a lithogenic diet leads to a marked decrease in expression of SR-BI in the murine gallbladder. 76 The expression of the above transporters is in agreement with a previous study that both cholesterol absorption and secretion occur on the apical side of GBECs.…”

“…Their transport directions are all derived from their function in liver and intestine. Studies on normal and diseased gallbladders have helped clinicians gain some insight into their functional role with respect to CGD, however, except for SR-BI, whose expression is restricted to the apical membrane of GBECs, 76 intracellular signals were noted for ABCG5/G8, 77 ABCA1, 78 megalin, and cubilin 73 by immunohistochemistry studies. These findings suggest a trafficking mechanism in their transport activity regulation.…”

“…Thus far, ATP-binding cassette transporters G5/G8 (ABCG5/G8), 72 megalin and cubilin, 73 scavenger receptor class B type I (SR-BI), 74 and ABCA1 75 have been reported to be expressed in GBECs. The obligate heterodimers ABCG5/G8 are expressed on the apical membrane of epithelial cells, where they excrete cholesterol into the lumen.…”