Lipin 2 is a Liver‐enriched Coactivator of Peroxisome Proliferator‐activated Receptor γ (PPARγ) Coactivator‐1α (PGC‐1α) and Regulates Fatty Acid Metabolism in Hepatocytes

Abstract

Lipin 1 acts in the nucleus to regulate gene expression via interactions with DNA‐bound nuclear receptor transcription factors and the PGC‐1α coactivator. Interestingly, lipin 1 also functions as an enzyme, catalyzing the penultimate step in triglyceride (TG) synthesis. However, little is known about the second lipin family member (lipin 2). We found that the expression of lipin 2 mRNA and protein was quite high in murine and human liver, but low in adipose tissue and skeletal muscle, where lipin 1 was enriched. The hepatic expression of lipin 1 and 2 was induced by fasting, but unlike lipin 1, the increase in lipin 2 was preserved in mice lacking PGC‐1α. Moreover, adenoviral‐driven PGC‐1α overexpression increased the expression of lipin 1, but not lipin 2, in hepatocytes. Nevertheless, lipin 2 protein physically interacted with and coactivated PPARα and PGC‐1α. Lipin 2 overexpression also augmented palmitate oxidation rates via increased expression of mitochondrial fatty acid oxidation enzymes. Rates of TG synthesis were surprisingly unchanged by overexpression of either lipin 1 or 2 in hepatocytes. These data indicate that lipin 2 is a liver‐enriched and fasting‐induced PGC‐1α activator. Furthermore, although the effects of lipin 1 and 2 on hepatic fatty acid metabolism significantly overlap, the expression of these two lipin genes is under the control of distinct regulatory circuits.