Oncostatin M regulates CYP7A1, the rate-limiting enzyme in bile acid biosynthesis, and contributes to the pathogenesis of non-alcoholic fatty liver disease

Background:

Oncostatin M (OSM) is an IL-6 family cytokine released by activated monocytes/macrophages, neutrophils and dendritic cells in the early phase of inflammatory processes. Recent studies using Osmr-/- mice determined a protective function of OSM in metabolic disorders. Increasing evidence suggests that hypercholesterolemia is a crucial factor in non-alcoholic fatty liver disease (NAFLD) pathogenesis. As Ldlr-/- mice are a physiological model of NAFLD and hypercholesterolemia we investigated the influence of OSM on NAFLD in genetic mouse models on C57/Bl6 and Ldlr-/- background.

Methods:

Eleven week old C57Bl/6, Osmr-/-, Ldlr-/- single and Ldlr-/-, Osmr-/- double knockout mice were fed a high fat, high cholesterol Western-type diet for 12 weeks. Body weight gain was determined on a weekly basis. After 12 weeks mice were sacrificed. Liver weight was evaluated; steatosis, cellular infiltrates and fibrosis were analyzed by immunohistochemistry. Expression of liver enzymes was monitored by qPCR analyses. Serum lipoproteins were measured by HPLC.

Results:

Osmr-/- mice were predisposed to body and liver weight gain upon Western-type diet, but were protected from weight gain when crossed with Ldlr-/- mice. As we expected hematoxylin/eosin and sudan IV staining of the liver tissues revealed enhanced lipid accumulation in Osmr-/- and Ldlr-/- compared to wild-type mice. Interestingly steatosis was reduced in Ldlr-/- Osmr-/- double knockout mice. Furthermore, Ldlr-/- Osmr-/- mice displayed lower blood glucose levels as well as serum cholesterol levels. Consistent with recent publications LDLR expression was downregulated in Osmr-/- mice. Transporters involved in cholesterol secretion at the canalicular membrane (ABCG5, ABCG8) did not display any significant differences between the genotypes. On the contrary, expression of the key enzyme of classical bile acid synthesis, CYP7A1, was strongly upregulated in Ldlr-/- Osmr-/- double compared to Ldlr-/- single knockout mice.

Conclusion:

Depending on the genetic background and metabolic status OSM appears to exert protective or pathogenic influences on the pathogenesis of NAFLD. Under hypercholesterolemia conditions OSM influences the expression of enzymes involved in bile acid synthesis and alters cholesterol clearence leading to reduced serum cholesterol levels in Ldlr-/- Osmr-/- animals. Further in depth characterization of the mouse models is required to understand the exact molecular mechanisms and therefore to clarify if OSM indeed might serve as a therapeutic agent for the treatment of obesity and related metabolic disorders as recently suggested.