(Pro)Renin Receptor Antagonism Attenuates High-Fat-Die-Induced Hepatic Steatosis in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we hypothesized that inhibition of the PRR would prevent the development of diet-induced hepatic steatosis and fibrosis. To test our hypothesis, we fed wild-type mice on a C57Bl/6J background either a high-fat diet (HFD; 60% calories from fat) or normal fat diet (NFD; 10% calories from fat) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis in C57BL/6J mice. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either PRO20, a peptide PRR antagonist, or scrambled peptide (700 g/kg/d) for 4 or 6 weeks. We found that a 6-week HFD significantly increased liver lipid accumulation, as detected by Oil Red O staining, and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment significantly reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or glucose levels. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area detected by Sirius Red staining was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase (ALT), an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPAR{gamma} and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the mechanism by which PRR regulates lipid metabolism in the liver and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis development in NAFLD.