RESUMO
Insig-2 is an ER membrane protein negatively controlling lipid biosynthesis. Here, we find that Insig-2 is increased in the tissues, including liver, but unaltered in the muscle of gp78-deficient mice. In hepatocytes and undifferentiated C2C12 myoblasts, Insig-2 is ubiquitylated on Cys215 by gp78 and degraded. However, the C215 residue is oxidized by elevated reactive oxygen species (ROS) during C2C12 myoblasts differentiating into myotubes, preventing Insig-2 from ubiquitylation and degradation. The stabilized Insig-2 downregulates lipogenesis through inhibiting the SREBP pathway, helping to channel the carbon flux to ATP generation and protecting myotubes from lipid over-accumulation. Evolutionary analysis shows that the YECK (in which C represents Cys215 in human Insig-2) tetrapeptide sequence in Insig-2 is highly conserved in amniotes but not in aquatic amphibians and fishes, suggesting it may have been shaped by differential selection. Together, this study suggests that competitive oxidation-ubiquitylation on Cys215 of Insig-2 senses ROS and prevents muscle cells from lipid accumulation.
Assuntos
Cisteína/metabolismo , Proteínas de Membrana/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Ubiquitinação , Anfíbios , Animais , Células CHO , Linhagem Celular , Cricetulus , Regulação para Baixo , Evolução Molecular , Peixes , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipogênese , Fígado/metabolismo , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Receptores do Fator Autócrino de Motilidade/genética , Análise de Sequência de Proteína , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , TranscriptomaRESUMO
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78-kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down-regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1ß. CONCLUSION: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936-1947).
