title: TAK1 regulates hepatic lipid homeostasis through SREBP.
abstract: Sterol-regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through transforming growth factor-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Morioka
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.|Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sai
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: E
authors.initials: E
authors.lastname: Omori
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding; D034622:RNA Interference; D012307:Risk Factors; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D051779:Sterol Regulatory Element Binding Proteins; D000099151:MAP Kinase Kinase Kinase 7