OSR1 Plays a Hepatoprotective Role in High-Fat Diet Induced Non-Alcoholic Fatty Liver Disease
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Date
2019-11-20
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Abstract
Obesity has increased significantly in recent decades and is widely considered a leading global health concern. This pandemic bears related chronic diseases that negatively influence health outcomes, substantially expends healthcare resources, and decreases quality of life. A major condition associated with obesity is non-alcoholic fatty liver disease. NAFLD, regarded as the hepatic manifestation of metabolic syndrome, is the most common form of liver disease in the United States and is expected to increase in prevalence parallel to obesity. NAFLD is a spectrum of diseased liver conditions ranging from simple steatosis, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The Odd-skipped related 1 gene encodes a putative transcription factor that reportedly plays a critical role in embryonic development and as a cancer repressor gene. However, its role in the liver has never been explored. Using a transgenic mouse model, we aimed to study the unknown function that Osr1 occupies in the progression of NAFLD. To address this question, we adapted a high fat diet induced NAFLD paradigm on Osr1 heterozygous mice. Wildtype and Osr1 knockdown mice were fed a HFD treatment for 10 weeks. Although there were no differences observed in body weight gain or glucose tolerance between the two groups, Osr1 heterozygous mice exhibited more severe steatosis compared to wildtype.
When examining molecular signaling pathways involved, we observed that Osr1+/- mice demonstrated decreased IRS-2 expression, enhanced hepatic Akt/mTOR activity, and a significant overactivation of hepatic JNK and NF-κB signaling compared to WT mice. Upregulation of lipogenesis genes Srepb1, Ppar-γ, and Acc was detected in the Osr1 heterozygous group. Decreased bile acid synthesis markers were also detected in this group. Additionally, Osr1 knockdown mice had significantly higher expression of inflammatory markers Il-1β and TNF-α than WT mice. Consistently, F4/80 positive cells indicated significantly increased number of hepatic macrophages in Osr1+/- groups. Based on these findings, we conclude that the Odd-skipped related 1 gene serves inhibitory roles in lipogenesis and inflammation during the pathogenesis of NAFLD.
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NAFLD, NASH, OSR1