Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 α (HNF4α) pathways to regulate liver lipid metabolism

PLoS One. 2012;7(12):e51320. doi: 10.1371/journal.pone.0051320. Epub 2012 Dec 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • DNA Primers / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Humans
  • Immunoprecipitation
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Luciferases
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphatidate Phosphatase / metabolism*
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Transcription Factors

Substances

  • DNA Primers
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Nuclear Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Small Interfering
  • Trans-Activators
  • Transcription Factors
  • Luciferases
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase