MD2 deficiency prevents high‐fat diet‐induced AMPK suppression and lipid accumulation through regulating TBK1 in non‐alcoholic fatty liver disease

Background Non‐alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. Methods Wild‐type, Md2−/− and bone marrow reconstitution mice fed with high‐fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA‐seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. Results Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD‐mediated suppression of AMP‐activated protein kinase (AMPK). This preservation of AMPK in Md2‐deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2‐increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. Conclusion Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1‐AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non‐inflammatory function of MD2 and evidence for the important role of MD2 in NALFD. Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1‐AMPK/SREBP1 and lipid metabolism pathway. PA‐MD2 interaction activates TBK1, which directly inhibit AMPK to increase the downstream SREBP1 activity and lead to hepatic lipid accumulation in hepatocytes. (3) MD2‐mediated inflammatory factors in macrophages also contribute to hepatocyte lipid accumulation and injury via TBK1‐AMPK pathway.