Abstract
Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPARα), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPARα can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPARα agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifnγ and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPARα as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver.
Highlights
Liver X receptors (LXR) are transcription factors belonging to the nuclear receptor superfamily
We demonstrate that combined treatment by T0901317, a potent activator of LXR, and fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARa), alleviated insulin resistance and improved glucose tolerance
The liver triglyceride level with the combined treatment was significantly higher compared to that of control group (p,0.01) and T0901317-treated group (p,0.05), suggesting that combined treatment had a synergistic effect on hepatic steatosis in high fat diet-induced obese mice
Summary
Liver X receptors (LXR) are transcription factors belonging to the nuclear receptor superfamily. PPARa regulates the expression of a number of genes critical for lipid and lipoprotein metabolism, and PPARa ligand fibrates are used for the treatment of dyslipidemia due to their ability to lower plasma triglyceride levels and elevate HDL cholesterol levels. Both LXR and PPARa need to form heterodimers with retinoid X receptor (RXR) to initiate the expression of their target genes [3]. A tight cross-talk exists between LXR and PPARa [4,5]
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