MSP-dependent Ron receptor tyrosine kinase signaling reduces white adipose tissue expansion and suppresses hepatic lipid accumulation through an LXR-dependent pathway in ApoE(-/-) mice fed a high fat/high cholesterol diet

Abstract Non-alcoholic fatty liver disease (NAFLD) has become a global burden and the pathogenic mechanism is not well understood. The current study was undertaken to investigate a novel signaling pathway involved in attenuating the progression of NAFLD. To establish the role of Ron receptor signaling in NAFLD, Apolipoprotein E knockout (ApoE KO) and Ron receptor ApoE double knockout (DKO) mice maintained on a high fat/high cholesterol diet (HFHCD) for 18 weeks were evaluated. DKO mice showed increased epididymal white adipose tissue (eWAT) mass and type 2 diabetes. Gene expression profiling revealed that DKO eWAT had increased transcript expression of pro-inflammatory cytokines and hypoxia-regulated genes. 1H NMR analysis of blood serum from the HFHCD-fed animals demonstrated that DKO mice had higher levels of circulating free fatty acids which are known to trigger hepatocellular injury and the development of steatohepatitis. DKO mice demonstrated increased levels of circulating ALT and AST liver enzymes, which are key markers for liver injury. Additionally, livers obtained from DKO mice demonstrated increased hepatic lipid accumulation. Genes involved in fatty acid synthesis (srebp-1c, fas), reverse cholesterol transport (abca1), and bile acid synthesis (cyp7a1) were repressed in DKO mice which are all target genes of the liver X receptor (LXR) pathway. Lxr gene expression was also increased in HFHCD-fed ApoE KO mice. Furthermore, ApoE KO mice showed higher circulating levels of triglycerides. Altogether, Ron receptor signaling attenuates white adipose tissue dysfunction and provides insight into a possible mechanism underlying the ability of Ron to suppress hepatic lipid accumulation in mice challenged with dietary cholesterol.