Regulation of Lipoprotein Lipase by the Oxysterol Receptors, LXRα and LXRβ

Yuan Zhang,David J Mangelsdorf,Joyce J Repa,Karine Gauthier

doi:10.1074/jbc.m107823200

Abstract

Lipoprotein lipase (LPL) is a key enzyme for lipoprotein metabolism and is responsible for hydrolysis of triglycerides in circulating lipoproteins, releasing free fatty acids to peripheral tissues. In liver, LPL is also believed to promote uptake of high density lipoprotein (HDL)-cholesterol and thereby facilitate reverse cholesterol transport. In this study we show that the Lpl gene is a direct target of the oxysterol liver X receptor, LXRalpha. Mice fed diets containing high cholesterol or an LXR-selective agonist exhibited a significant increase in LPL expression in the liver and macrophages, but not in other tissues (e.g. adipose and muscle). Studies in Lxr-deficient mice confirmed that this response was dependent more on the presence of LXRalpha than LXRbeta. Analysis of the Lpl gene revealed the presence of a functional DR4 LXR response element in the intronic region between exons 1 and 2. This response element directly binds rexinoid receptor (RXR)/LXR heterodimers and is sufficient for rexinoid- and LXR agonist-induced transcription of the Lpl gene. Together, these studies further distinguish the roles of LXRalpha and beta and support a growing body of evidence that LXRs function as key regulators of lipid metabolism and are anti-atherogenic.

Highlights

Chylomicrons and very low density lipoprotein particles are the main carriers of triglycerides in plasma
Liver Lipoprotein lipase (LPL) Gene Expression Is Induced by Cholesterol and Synthetic rexinoid receptor (RXR)/LXR Agonists—Previous work has shown that the hepatic accumulation of triglycerides in cholesterol-fed mice is dependent on the expression of LXR␣ [25]
To explore the possibility that changes in hepatic LPL expression are associated with this response, wild-type, Lxr␣Ϫ/Ϫ, Lxr␤Ϫ/Ϫ, and Lxr␣/␤Ϫ/Ϫ mice were treated with various dietary regimens for 12 h or 7–10 days and sacrificed, and hepatic LPL expression was examined by Northern analysis

Summary

EXPERIMENTAL PROCEDURES

Materials—LG268, 22(R)-hydroxycholesterol, and T0901317 were acquired from Ligand Pharmaceuticals, Steraloids Inc., and Tularik, Inc, respectively. The rexinoid LG268 was solubilized at 4.5 mg/ml in a vehicle containing 0.9% carboxymethylcellulose, 9% polyethylene glycol 400, and 0.05% Tween 80 and provided in the diet to give a final concentration of 30 mg/kg body weight. The LXR agonist T0901317 was solubilized in a vehicle containing 1% methylcellulose and 1% Tween 80 and administered by oral gavage or provided in the diet at a dose of 50 mg/kg body weight. Northern Analysis—RNA was extracted and used in Northern analysis as described previously [25]. Cells were allowed to adhere for 7 h in DMEM containing10% fetal bovine serum and penicillin/streptomycin. The medium was replaced with DMEM supplemented with 10% lipoprotein-deficient serum, penicillin/streptomycin, and either vehicle (Me2SO) or 10 ␮M LXR agonist (T0901317) and incubated for 42 h. The gel was dried at 80 °C for 1.5 h and autoradiographed with intensifying screens at Ϫ80 °C overnight

RESULTS

LXR Regulation of Lipoprotein Lipase

DISCUSSION