Complex Interplay between the Lipin 1 and the Hepatocyte Nuclear Factor 4 α (HNF4α) 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 4 alpha (HNF4 alpha), which induces lipin 1 gene expression in cooperation with peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) 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 HNF4 alpha to activate the expression of a variety of genes encoding enzymes involved in fatty acid catabolism. In contrast, lipin 1 reduces the ability of HNF4 alpha to induce the expression of genes encoding apoproteins A4 and C3. Although the ability of lipin to diminish HNF4 alpha 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 HNF4 alpha in a promoter-independent context. Thus, the induction of lipin 1 by HNF4 alpha may serve as a mechanism to affect promoter selection to direct HNF4 alpha to promoters of genes encoding fatty acid oxidation enzymes.