The Absence of MSP‐Dependent Ron Receptor Tyrosine Kinase Signaling Promotes Unrestrained White Adipose Tissue Expansion, Exacerbated Hepatic Inflammation and Aberrant Hepatic Lipid Metabolism in ApoE −/− Mice Fed a High Fat/High Cholesterol Diet

In parallel with the growing epidemicof obesity, non‐alcoholic fatty liver disease (NAFLD) has shown a strong association to the metabolic disorder. One of the major burdens of fatty liver disease is its ability to progress to non‐alcoholic steatohepatitis which can provoke irreversible stages such as cirrhosis. To date, there are no specific therapies for targeting steatohepatitis and as a result the disease is one of the most common indications for liver transplantation. The current study was undertaken to investigate a novel signaling pathway involved in attenuating the progression of steatohepatitis in diet‐fed mice. We have previously demonstrated that the Ron receptor tyrosine kinase restrains inflammatory macrophage activation which is aphenotype known to drive the development and progression of steatohepatitis. To establish the role of Ron signaling in steatohepatitis, Apolipoprotein E knockout (ApoE KO) and Ron knockout ApoE knockout mice (DKO) maintained on a high fat/high cholesterol diet (HFHCD) for 18 weeks were evaluated. There were no significant differences in body weight among the groups of mice. Although body weights were similar among the HFHCD‐fed mice, the distribution of fat depots differed. ApoE KO mice deficient in MSP‐dependent Ron receptor signaling (DKO) showed increased and unrestrained accumulation of epididymal white adipose tissue. The unrestrained expansion of visceral white adipose tissue was matched with fasting hyperglycemia and impaired glucose tolerance. Gene expression profiling reveals that DKO white adipose tissue has a specific inflammatory signature which includes increased transcript expression of pro‐inflammatory cytokines and hypoxia‐regulated genes. 1 H Nuclear magnetic resonance (NMR) analysis of blood serum derived from the HFHCD‐fed animals demonstrated that DKO mice had higher levels of circulating fatty acids when compared to ApoE KO control mice. Increased levels of circulating very low density lipoproteins (VLDL)/low density lipoproteins (LDL) were also observed in DKO mice maintained on diet. Although no differences were observed for liver weights, HFHCD‐fed DKO mice demonstrated increased levels of circulating alaninetransaminase (ALT) and aspartate transaminase (AST), which are key markers for chronic liver injury. Furthermore, DKO mice showed higher levels of additional serological markers associated with chronic liver disease including bilirubin, globulin, and total protein. Additionally, livers obtained from DKO mice demonstrated increased inflammation, impaired lipid metabolism, and decreased cholesterol efflux. Altogether, the presence of MSP‐dependent Ron receptor signaling ameliorates white adipose tissue dysfunction, steatohepatitis, and associated metabolic features such as glucose intolerance. Our group has also shown that activated Ron receptor signaling attenuates obesity and atherosclerosis using diet‐induced non‐transgenic and transgenic mouse models. Obesity, steatohepatitis and atherosclerosis are tightly linked diseases. Therefore, manipulation of Ron receptor activation can serve as an effective strategy for improving the prognosis of these diseases simultaneously. Support or Funding Information This study was supported by the College of Agricultural Sciences Department of Veterinary and Biomedical Sciences of The Pennsylvania State University and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number 2T32AI074551‐06.