title: TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.
abstract: The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Inokuchi-Shimizu
authors.forename: Eek Joong
authors.initials: EJ
authors.lastname: Park
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Roh
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Bi
authors.initials: B
authors.lastname: Zhang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Song
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Michael
authors.initials: M
authors.lastname: Pimienta
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Kinji
authors.initials: K
authors.lastname: Asahina
authors.forename: William
authors.initials: W
authors.lastname: Lagakos
authors.forename: Mason R
authors.initials: MR
authors.lastname: Mackey
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Dorothy D
authors.initials: DD
authors.lastname: Sears
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055372:AMP-Activated Protein Kinases; D005227:Fatty Acids; D020930:MAP Kinase Kinase Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D047493:PPAR alpha; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7