title: TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions.
abstract: Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P=9.39 × 10(-7)) associated with ultrasonographically diagnosed non-alcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan Department of Anatomy Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi 329-0498, Japan Health Care Food Research, Human Health Care Research, Research and Development, Kao Corporation, Sumida-ku, Tokyo 131-8501, Japan Jichi Medical University Health Care Center, Shimotsuke-shi, Tochigi 329-0498, Japan Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Yuumi
authors.initials: Y
authors.lastname: Ishizuka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ogawa
authors.forename: Saho
authors.initials: S
authors.lastname: Makishima
authors.forename: Supichaya
authors.initials: S
authors.lastname: Boonvisut
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yanagisawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyashita
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D004734:Energy Metabolism; D005234:Fatty Liver / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D014463:Ultrasonography
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C493170:TRIB1 protein, human; C523598:Trib1 protein, mouse; D014280:Triglycerides; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases
keywords: fats/fatty acids; hyperlipidemia; liver; metabolism; molecular genetics