Human SREBP1c Expression in Liver Is Directly Regulated by Peroxisome Proliferator-activated Receptor α (PPARα)

Abstract

Sterol regulatory element binding proteins (SREBPs) regulate the expression of a number of enzymes, which catalyze the synthesis of fatty acids, cholesterol, triglycerides, and phospholipids. SREBP1c is the most relevant isoform in the adult liver, and its expression is controlled by the nutritional state. Transcriptional regulation studies into the SREBP1c gene, performed in the last few years, have improved our knowledge of the variability of signals that converge on its promoter region. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. The present study aimed to perform a detailed analysis of the human SREBP1c gene promoter structure in liver cells by focusing on responses to diverse metabolic signals. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. We discovered that peroxisome proliferation-activated receptor alpha (PPARα) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at -453 in the human promoter was involved in this activation. Moreover, PPARα agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPARα as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation.