Piperine, an LXRα antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet

This study investigated the role of piperine in the transcriptional regulation of liver X receptor alpha (LXR alpha) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXR alpha activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRa and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXR alpha mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBP alpha, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2 alpha, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXR alpha transcriptional activity by abolishing the interaction of ligand-bound LXR alpha with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXR alpha-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD. (C) 2012 Elsevier Inc. All rights reserved.