title: Hepatic Elovl6 gene expression is regulated by the synergistic action of ChREBP and SREBP-1c.
abstract: Elongation of very long chain fatty acids protein 6 (ELOVL6), a rate-limiting enzyme for the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons, plays a key role in energy metabolism and insulin sensitivity. Hepatic Elovl6 expression is upregulated in the fasting-refeeding response and in leptin-deficient ob/ob mice. Mouse Elovl6 has been shown to be a direct target of sterol regulatory element binding protein-1 (SREBP-1) in response to insulin. In the present study, we demonstrated that mouse and human Elovl6 expression is under the direct transcriptional control of carbohydrate response element binding protein (ChREBP), a mediator of glucose-induced gene expression. Serial deletion and site-directed mutagenesis studies revealed functional carbohydrate response elements (ChoREs) in the mouse and human Elovl6 promoters and gel shift assays and chromatin immunoprecipitation assays confirmed the binding of ChREBP to the Elovl6-ChoRE sites. In addition, the ectopic co-expression of ChREBP and SREBP-1c in HepG2 cells synergistically stimulated Elovl6 promoter activity and this synergistic activation was abolished by mutating the Elovl6 promoter ChoREs. Taken together, these results suggest that the synergistic action of ChREBP and SREBP-1c is necessary for the maximal induction of Elovl6 expression in the liver.
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Jin-Sik
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Oh
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Incheon 21565, Republic of Korea. Electronic address: jycha1014@gachon.ac.kr.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Cha
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000081031:Fatty Acid Elongases; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
keywords: Carbohydrate; ChREBP; Elovl6; SREBP-1c; Transcriptional regulation