title: Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 α (HNF4α) pathways to regulate liver lipid metabolism.
abstract: Lipin 1 is a bifunctional protein that serves as a metabolic enzyme in the triglyceride synthesis pathway and regulates gene expression through direct protein-protein interactions with DNA-bound transcription factors in liver. Herein, we demonstrate that lipin 1 is a target gene of the hepatocyte nuclear factor 4α (HNF4α), which induces lipin 1 gene expression in cooperation with peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) through a nuclear receptor response element in the first intron of the lipin 1 gene. The results of a series of gain-of-function and loss-of-function studies demonstrate that lipin 1 coactivates HNF4α to activate the expression of a variety of genes encoding enzymes involved in fatty acid catabolism. In contrast, lipin 1 reduces the ability of HNF4α to induce the expression of genes encoding apoproteins A4 and C3. Although the ability of lipin to diminish HNF4α activity on these promoters required a direct physical interaction between the two proteins, lipin 1 did not occupy the promoters of the repressed genes and enhances the intrinsic activity of HNF4α in a promoter-independent context. Thus, the induction of lipin 1 by HNF4α may serve as a mechanism to affect promoter selection to direct HNF4α to promoters of genes encoding fatty acid oxidation enzymes.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Gropler
authors.forename: Mayurranjan S
authors.initials: MS
authors.lastname: Mitra
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D017931:DNA Primers; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D008156:Luciferases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase