Abstract
The liver X receptors (LXRs) sense oxysterols and regulate genes involved in cholesterol metabolism. Synthetic agonists of LXRs are potent stimulators of fatty acid synthesis, which is mediated largely by sterol regulatory element-binding protein-1c (SREBP-1c). Paradoxically, an improved hepatic lipid profile by LXR was observed in mice fed a Western high fat (HF) diet. To explore the underlying mechanism, we administered mice normal chow or an HF diet and overexpressed LXRalpha in the liver. The HF diet with tail-vein injection of adenovirus of LXRalpha increased the expression of LXR-targeted genes involved in cholesterol reverse transport but not those involved in fatty acid synthesis. A similar effect was also observed with the use of 22R-hydroxycholesterol, an LXR ligand, in cultured hepatocytes. Consequently, SREBP-1c maturation was inhibited by the HF diet, which resulted from the induction of Insig-2a. Importantly, increased cholesterol level suppressed the expression of 2,3-oxidosqualene cyclase (OSC), which led to an increase in endogenous LXR ligand(s). Furthermore, siRNA-mediated knockdown of OSC expression enhanced LXR activity and selectively up-regulated LXR-targeted genes involved in cholesterol reverse transport. Thus, down-regulation of OSC may account for a novel mechanism underlying the LXR-mediated lipid metabolism in the liver of mice fed an HF diet.
Highlights
The liver X receptors (LXRs),2 including LXR␣ and LXR, are members of the nuclear receptor superfamily of transcription factors
SREBPs are cleaved in the Golgi apparatus to release their amino acid termini, which translocate to the nucleus, where they bind to the sterol regulatory element (SRE) in the promoters of various target genes
LXR␣ and Its Ligand Differentially Regulate the Expression of LXR␣-targeted Genes—Given that an high fat (HF) diet may provide endogenous ligand(s) of LXR to selectively up-regulate genes involved in reverse cholesterol transport, we examined the effect of LXR␣ and oxysterol, an endogenous LXR ligand, on the expression of LXR␣-targeted genes
Summary
Body weight (g) LW/BW (%) Liver chol (mg/g) Liver TG (mg/g) Blood glucose (mmol/l) Plasma insulin (mU/ml) HOMA-IR. The blood samples were withdrawn from the mouse saphenous vein, and plasma insulin concentrations were measured by use of an ultrasensitive I125-linked immunosorbent assay kit (Fu Rui Inc., Beijing, China). Data are mean Ϯ S.E. of the mRNA levels normalized to that of -actin and expressed as fold of that of GFP-infected specimens (*, p Ͻ 0.05). Data are mean Ϯ S.E. of the relative luciferase activities from three independent experiments, each performed in triplicate (*, p Ͻ 0.05; **, p Ͻ 0.01). PSIREN-OSC plasmid was delivered by use of a modified hydrodynamic transfection method as described previously [29]. The amount of plasma lipoproteins in serum or the control 22S-HC (Sigma) was added into samples before the FPLC fractions was detected by use of an automated clinical lipid extraction. All results are expressed as mean Ϯ S.E. from at least three independent experiments. p Ͻ 0.05 was considered statistically significant
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