The ghrelin/leptin imbalance during cholestasis is driven by peripheral S1P2R‐dependent bile acid signaling

During the course of chronic cholestatic liver diseases cholangiocytes exhibit marked proliferative capacity followed by cholangiocyte loss. Dysregulation in the hormones controlling energy expenditure and food intake have been demonstrated as a consequence of cholestatic liver diseases. Specifically, in patients with primary biliary cirrhosis, circulating leptin levels are increased whereas, ghrelin, its counterpart, is decreased, although the cause of this imbalance is largely unknown. Increased serum bile acids are a key feature of cholestasis and are blamed for some of the extrahepatic consequences of these diseases. Bile acids are capable of signaling via a number of receptors including the sphingosine‐1 phosphate 2 receptor (S1P2R). The aims of this study were to assess the role of bile acid signaling in the imbalance between ghrelin and leptin. In a rat model of cholestasis (bile duct ligation; BDL) circulating levels of leptin was increased and ghrelin levels were suppressed. Ghrelin and leptin are weakly expressed in the liver and expression levels are unchanged during cholestasis, suggesting that ghrelin and leptin are originating from extrahepatic sources. Total ghrelin protein in the stomach was decreased after BDL surgery, as was the protein required for bioactivation of ghrelin (ghrelin O‐acyltransferase; GOAT). Furthermore, treatment with recombinant ghrelin decreased cholangiocyte proliferation (as assessed by cytokeratin‐19 expression) and markers of biliary fibrosis (a‐smooth muscle actin, collagen 1a1, and fibronectin 1) after BDL. Conversely, leptin expression in adipose tissue was increased after BDL and contributed to cholangiocyte proliferation and fibrosis. The imbalance between ghrelin and leptin after BDL could be attenuated in rats fed a diet enriched in the bile acid sequestrant cholestyramine. In vitro , treatment of mouse gastric ghrelin‐expressing cells with the conjugated bile acids taurocholic acid (TCA) and glycochenodeoxycholic acid (GCDA) inhibited ghrelin mRNA expression and could be prevented by pretreatment with the S1P2R antagonist JTE013. Similarly, the S1P2R antagonist prevented TCA‐induced upregulation of leptin in differentiated adipocytes. Taken together our data supports the observation that an imbalance between ghrelin and leptin exists during cholestasis that contributes to the resulting liver pathology. Furthermore our data suggests that this imbalance is as a consequence of S1P2R‐mediated bile acid signaling in the periphery. Support or Funding Information The following study was funded by an NIH R01 award (DK082435), and a VA Merit award (BX002638‐01) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (BLR&D) to Dr. DeMorrow