Abstract
The liver X receptors, LXRalpha (NR1H3) and LXRbeta (NR1H2), are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRs play a critical role in cholesterol homeostasis and bile acid metabolism. In addition, oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia. This increased hepatic lipogenesis has been largely attributed to the LXR-dependent up-regulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression. However, it has been reported that treating Srebp-1c null mice with the synthetic LXR agonist T0901317 still results in enhanced expression of many lipogenic genes, suggesting additional mechanisms by which LXR can enhance hepatic lipogenesis. In this report, we identify the carbohydrate response element-binding protein (ChREBP) as an LXR target that independently enhances the up-regulation of select lipogenic genes. The ChREBP promoter contains functional LXR-binding sites that confer receptor-dependent binding and transactivation. We show that T0901317 treatment of mice is associated with up-regulation of the ChREBP target gene, liver-type pyruvate kinase. Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates ChREBP activity. This establishes LXR as a master lipogenic transcription factor, as it directly regulates both SREBP-1c and ChREBP to enhance hepatic fatty acid synthesis.
Highlights
Members of the nuclear hormone receptor superfamily function as ligand-activated transcription factors to regulate genes critical to development, reproduction, and intermediary metabolism [1]
Oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia
In addition to an increase in hepatic carbohydrate response element-binding protein (ChREBP) mRNA, there is a concomitant increase in liver-type pyruvate kinase (L-PK) mRNA indicative mpk, milligrams/kilograms body weight; PXR, pregnane X receptor; RXR, retinoid X receptor; SCD-1, stearoyl-CoA desaturase; SREBP-1c, sterol regulatory element-binding protein 1c; LXR-responsive elements (LXREs), LXR-responsive element; qRT, quantitative real-time; DKO, double knock-out; ACC, acetyl-CoA carboxylase; Chromatin Immunoprecipitation (ChIP), chromatin immunoprecipitation
Summary
T0901317 was purchased from Cayman Chemical Co. (Ann Arbor, MI). LG268 was provided by Richard Heyman and Mark Leibowitz of Ligand Pharmaceuticals (La Jolla, CA). Roger Unger (University of Texas, Southwestern) provided troglitazone. All other nuclear receptor agonists were purchased from Sigma. ChREBP-knock-out mice were kindly provided by Kosaku Uyeda (University of Texas, Southwestern [15]). Male Agouti 129/SvJ mice at 3 months of age were provided with the meal form of a standard rodent diet (diet number 7001, Harlan Teklad Premier Laboratory Diets, Madison, WI) supplemented with various nuclear receptor agonists, during a 12-h dark cycle. Male mice (Agouti 129/SvJ, C57Bl/6, or Chrebp knock-out [15]) received T0901317 (LXR agonist, 50 mg/kg body weight (mpk)) or vehicle (0.9% carboxymethylcellulose, 9% polyethylene glycol 400, and 0.05% Tween 80) by oral gavage each day for 3 to 10 days as described for each study in the figure legends. At the end of the dietary treatments, mice were anesthetized, exsanguinated via the descending vena cava, and tissues removed and flash-frozen in liquid nitrogen
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