Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 alpha (HNF4alpha) pathways to regulate liver lipid metabolism

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 4a (HNF4a), which induces lipin 1 gene expression in cooperation with peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) 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-offunction studies demonstrate that lipin 1 coactivates HNF4a to activate the expression of a variety of genes encoding enzymes involved in fatty acid catabolism. In contrast, lipin 1 reduces the ability of HNF4a to induce the expression of genes encoding apoproteins A4 and C3. Although the ability of lipin to diminish HNF4a 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 HNF4a in a promoter-independent context. Thus, the induction of lipin 1 by HNF4a may serve as a mechanism to affect promoter selection to direct HNF4a to promoters of genes encoding fatty acid oxidation enzymes. Citation: Chen Z, Gropler MC, Mitra MS, Finck BN (2012) Complex Interplay between the Lipin 1 and the Hepatocyte Nuclear Factor 4 a (HNF4a) Pathways to Regulate Liver Lipid Metabolism. PLoS ONE 7(12): e51320. doi:10.1371/journal.pone.0051320 Editor: Makoto Makishima, Nihon University School of Medicine, Japan Received July 16, 2012; Accepted October 31, 2012; Published December 7, 2012 Copyright: 2012 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was also supported by the National Institutes of Health grant R01 DK78187 (to BNF) and was also supported, in part, by the Digestive Diseases Research Core Center (P30 DK52574) and the Nutrition Obesity Research Center (NORC) (P30 DK56341) of Washington University School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]