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 (PPAR␣) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at ؊453 in the human promoter was involved in this activation. Moreover, PPAR␣ agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPAR␣ as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation.The prevalence of overweight and obesity is increasing worldwide at an alarming rate. An excess amount of body fat not only leads to reduced quality of life and immense healthcare-associated costs but also increases risk of death. Indeed, obesity has been related to a number of cardiovascular and metabolic disorders such as hypertension, type 2 diabetes, hyperinsulinemia, dyslipidemia, and atherosclerosis, all of them defining features of the metabolic syndrome. Beyond obesity and a number of independent factors, the other etiological factor of metabolic syndrome is insulin resistance, commonly considered to be of greater priority in pathogenesis (1, 2).The discovery of sterol regulatory element binding proteins (SREBPs) 4 was critical for our understanding of hepatic cholesterol homeostasis. SREBP1c, one of three SREBPs members of the basic helix-loop-helix family of transcription factors, is essential for the genomic actions of insulin on both carbohydrate and lipid metabolism (3) and plays a central role in the molecular biochemistry of metabolic syndrome. The SREBP1c expression is controlled by nutritional status. Fasting lowers SREBP1c mRNA and protein levels, whereas they are strongly induced in a fed state, followed by a compatible pattern of nutritional changes in lipogenic genes (4). Accordingly, changes in the activity of this transcription factor may be the key to linking insulin resistance with other obesity-associated metabolic disorders.Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily. The LXR subfamily co...

Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan, on non-alcoholic steatohepatitis using FLS-ob/ob male mice

“…Irbesartan upregulates hepatic expression of PPAR-α (25) and hepatic SREBP1c expression is directly regulated by PPAR-α (26). The present study also showed upregulated PPAR-α gene expression.…”

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

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“…It is known that activation of PPAR under dyslipidemic condition modulates the expression of transcriptional factors SEBP1-c (sterol regulatory element binding protein-1) and ChREBP (carbohydrate regulatory element binding protein), which regulate almost all genes involved in biosynthesis of FA, TAG and phospholipids [22,23]. According to the data that we have already obtained (compensatory action of NSE on the liver phospholipid and fatty acid composition of rats with IR), we suggest Values represented mean ± SEM.…”