title: Identification of MIG12 as a mediator for stimulation of lipogenesis by LXR activation.
abstract: Liver X receptor (LXR)α and LXRβ belong to the nuclear receptor superfamily and play central roles in the transcriptional control of lipid metabolism. We describe a novel LXR target, midline-1-interacting G12-like protein (MIG12), which has been recently identified as an acetyl-coenzyme A carboxylase-binding protein. The binding causes the induction of de novo fatty acid (FA) synthesis through the activation of acetyl-coenzyme A carboxylase (a rate-limiting enzyme for de novo FA synthesis). Luciferase reporter gene assays using the MIG12 gene promoter revealed the existence of a LXR-responsive element (LXRE) and carbohydrate-responsive element-binding protein (ChREBP)-responsive element named LXRE3 and carbohydrate response element 1, respectively. Deletion and mutation of LXRE3 and carbohydrate response element 1 abolished LXR and ChREBP responsiveness, respectively. Electrophoretic mobility shift assays demonstrated that the LXRα/retinoid X receptor α complex was bound to LXRE3. Treatment with high glucose concentration, which leads ChREBP activation, or LXR activator stimulated MIG12 expression in rat primary hepatocytes, and combined treatment further stimulated MIG12 expression. Furthermore, hepatic expression of MIG12 in mice was induced by refeeding. Overexpression of MIG12 stimulated and knockdown of MIG12 attenuated LXR ligand-stimulated de novo FA synthesis and triacylglycerol accumulation. These results indicate that MIG12 is a mediator for stimulation of lipogenesis by LXR activation in the liver.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Emina
authors.initials: E
authors.lastname: Ikeuchi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Satoh
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D005227:Fatty Acids / Q000096:biosynthesis; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050155:Lipogenesis / Q000235:genetics*; D000071518:Liver X Receptors; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008156:Luciferases; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D014157:Transcription Factors; D014280:Triglycerides; C485294:Mig12 protein, mouse; C506001:Mlxipl protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides