Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation

Abstract

The Gpbar1 [G-protein-coupled BA (bile acid) receptor 1] is a recently identified cell-surface receptor that can bind and is activated by BAs, but its physiological role is unclear. Using targeted deletion of the Gpbar1 gene in mice, we show that the gene plays a critical role in the maintenance of bile lipid homoeostasis. Mice lacking Gpbar1 expression were viable, developed normally and did not show significant difference in the levels of cholesterol, BAs or any other bile constituents. However, they did not form cholesterol gallstones when fed a cholic acid-containing high-fat diet, and liver-specific gene expression indicated that Gpbar1-deficient mice have altered feedback regulation of BA synthesis. These results suggest that Gpbar1 plays a critical role in the formation of gallstones, possibly via a regulatory mechanism involving the cholesterol 7alpha-hydroxylase pathway.

A Membrane-proximal, C-terminal α-Helix Is Required for Plasma Membrane Localization and Function of the G Protein-coupled Receptor (GPCR) TGR5

“…4 that is expressed almost ubiquitously in humans and rodents (1)(2)(3)(4). The receptor is coupled to a stimulatory G protein.…”

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

“…Such data are relevant especially given the recent interest in FXR or TGR5 agonists for the treatment of metabolic disease [20]. The tissue expressing the highest levels of TGR5 is the gallbladder; interestingly, TGR5 knockout mice are protected from cholesterol gallstone development [21]. Therefore, treatment strategies using TGR5 agonists might be associated with an increased incidence of cholesterol gallstones.…”

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

“…In mice, it is predominantly expressed in the gallbladder (Vassileva et al 2006), but also in gastrointestinal tract, lung, heart, ovary, placenta, white adipose tissue (WAT), and brown adipose tissue (BAT; Maruyama et al 2002, Kawamata et al 2003, Vassileva et al 2006. In mouse gallbladder, the expression level of Gpbar1 mRNA is 60-100 times greater than that of Gpbar1 mRNA in all other tissues analyzed, and in situ hybridization has shown that it is restricted to epithelial cells (Vassileva et al 2006). Recently, GPBAR1 protein was localized to liver sinusoidal endothelial cells and Kupffer cells in rat (Keitel et al 2007(Keitel et al , 2008a, and gallbladder epithelium in human (Keitel et al 2009).…”