TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions
| Autor: | Yuumi Ishizuka, Kazuhiro Nakayama, Ayumi Ogawa, Saho Makishima, Supichaya Boonvisut, Atsushi Hirao, Yusaku Iwasaki, Toshihiko Yada, Yoshiko Yanagisawa, Hiroshi Miyashita, Masafumi Takahashi, Sadahiko Iwamoto |
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| Rok vydání: | 2014 |
| Předmět: |
Blood Glucose
Male Blotting Western Population Down-Regulation Protein Serine-Threonine Kinases Regulatory Sequences Nucleic Acid Biology Polymorphism Single Nucleotide Mice Endocrinology Genes Reporter Non-alcoholic Fatty Liver Disease Enhancer binding CEBPA CEBPB Animals Humans RNA Messenger education Molecular Biology Triglycerides Ultrasonography education.field_of_study Reporter gene Gene knockdown Lipogenesis Intracellular Signaling Peptides and Proteins Organ Size Molecular biology DNA-Binding Proteins Fatty Liver Liver Glycogenesis Gene Knockdown Techniques Female Energy Metabolism Transcriptome Glycogen Protein Binding Signal Transduction |
| Zdroj: | Journal of Molecular Endocrinology. 52:145-158 |
| ISSN: | 1479-6813 0952-5041 |
| DOI: | 10.1530/jme-13-0243 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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