Dipeptidyl Peptidase 4-Deficient Rats Have Improved Bile Secretory Function in High Fat Diet-Induced Steatosis

Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury. Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters. DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures. Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.