RRC ID 70154
Author Luo W, Ye L, Hu XT, Wang MH, Wang MX, Jin LM, Xiao ZX, Qian JC, Wang Y, Zuo W, Huang LJ, Liang G.
Title MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease.
Journal Clin Transl Med
Abstract 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.
Volume 12(3)
Pages e777
Published 2022-3-1
DOI 10.1002/ctm2.777
PMID 35343085
PMC PMC8958353
MeSH AMP-Activated Protein Kinases / genetics AMP-Activated Protein Kinases / metabolism Animals Diet, High-Fat* / adverse effects Lipids / adverse effects Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease* / genetics Non-alcoholic Fatty Liver Disease* / metabolism Protein Serine-Threonine Kinases / genetics
Mice RBRC02388