Apoe- vs. Ldlr-KO: The genetic background determines the function of Oncostatin M in the regulation of lipid homeostasis

Background:

Oncostatin M (OSM) is a member of the interleukin-6-type cytokine family, which plays a pivotal role not only in inflammatory processes including the acute phase response, but also in the regulation of metabolic processes. Although pathogenetically not entirely elucidated, growing evidence emphasizes the importance of OSM in the highly prevalent metabolic syndrome. Previous studies revealed increased body weight, hepatic steatosis and insulin resistance in OSM receptor beta-deficient aged mice on chow diet. On high-fat diet, these effects were even more pronounced.

Question:

To investigate the metabolic features of Oncostatin M in two different mouse models prone to atherosclerosis and liver steatosis.

Methods:

We employed Apoe-/- and Ldlr-/- single knockout as well as Ldlr-/-Osmr-/- and Apoe-/-Osmr-/- double knockout mice. Mice were fed a Western-type diet for 12 weeks. Thereafter, mice were sacrificed and serum lipid levels were measured by using enzymatic assays and lipoprotein fractions were determined by performing HPLC analyses. Hepatic lipid content was studied following Folch's lipid extraction protocol. Gene expression analyses of adipose and liver tissue were carried out using the RT-qPCR.

Results:

Interestingly, Ldlr-/- single knockout mice exhibited the most pronounced weight gain during the Western-type diet, fitting to increased expression levels of the very-low-densitiy-lipoprotein receptor in adipose tissue. Lipid assays revealed a contrasting impact of Osmr deficiency on serum levels of cholesterol, non-esterified free fatty acids and triglycerides in the background of Apoe-/- and Ldlr-/- mice. Intriguingly, rather total cholesterol levels than serum lipoprotein fractions appeared to be affected since VLDL/LDL/HDL distribution differed just slightly within each group and its respective Osmr-/- correlate. Besides, similar trends in altered cholesterol and triglyceride homeostasis were found in the livers of our mice. Differently regulated inflammatory markers of liver and adipose tissue imply a complex interplay between lipid metabolism and inflammation.

Conclusion:

Depending on the genetic background, OSM appears to be protective or pathogenic in the development dyslipidemia. Our experiments indicate that the level of inflammation plays a crucial role in this decision. Further in depth characterization of the mouse models is required to understand the underlying molecular mechanisms.