Deficiency of the oncostatin M receptor affects the pathogenesis of non-alcoholic fatty liver disease in a context dependent manner

Background:

The early phase of inflammation is characterized by the release of cytokines/chemokines from activated neutrophils, monocytes and dendritic cells. One of the most strongly secreted cytokines is the interleukin-6-type cytokine oncostatin M (OSM). Since OSM itself is a strong inducer of chemokines, particularly in tissue-resident cell types like fibroblasts, it is considered to promote the inflammatory response. Surprisingly, it has recently been shown to execute protective functions in high-fat diet-induced obesity and related metabolic disorders in mice. Its role in the development of non-alcoholic fatty liver disease (NAFLD) and in conjunction with hypercholesterolemia, however, has not been addressed so far.

Methods:

C57Bl/6, Osmr-/-, Ldlr-/- single knockout and Ldlr-/-, Osmr-/- double knockout mice were fed a high-fat diet for 12 weeks. Weight gain was documented on a weekly basis. After 12 weeks mice were sacrificed. Liver weight was evaluated; steatosis and cellular composition were analyzed by immunohistochemistry. Serum levels of cholesterol and leptin were determined by HPLC and ELISA, respectively. Expression of liver enzymes was monitored by qPCR analyses.

Results:

Confirming the published results, Osmr-/- mice gained significantly more body and liver weight in contrast to C57Bl/6 mice. Serum cholesterol levels were increased more than two-fold in knockout compared to wild-type animals. However, on an Ldlr-/- background displaying hypercholesterolemia the phenotype was reversed and Ldlr-/- Osmr-/- double knockout mice gained less body and liver weight, showed lower blood glucose levels as well as serum cholesterol and leptin levels. Preliminary analyses of liver enzymes indicated a reduction in the expression of enzymes involved in fatty acid synthesis (Fasn, Elovl6, Acc, Scd1), no differences in long-chain acyl-coenzyme A synthetases (Acsl), but altered cholesterol metabolism in Ldlr-/- Osmr-/- double knockout mice.

Conclusion:

OSM exerts protective as well as pathogenic influences on the establishment of fatty liver disease depending on the genetic background and metabolic status. Further in depth characterization of the different mouse models will help to dissect the molecular mechanisms underlying this ambivalence. Thereby, this study will help to clarify if OSM might indeed serve as a therapeutic agent for the treatment of obesity and related metabolic disorders as recently suggested.

Corresponding author: Hermanns, Heike M.

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