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. 2000 Nov 15;14(22):2831-8.
doi: 10.1101/gad.850400.

"VSports最新版本" Role of LXRs in control of lipogenesis

J R Schultz  1 , H Tu, A Luk, J J Repa, J C Medina, L Li, S Schwendner, S Wang, M Thoolen, D J Mangelsdorf, K D Lustig, B Shan
Affiliations

Role of LXRs in control of lipogenesis

J R Schultz et al. Genes Dev. .

Abstract

The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metabolism VSports手机版. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiological role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species. Complementary studies in cell culture and animals suggested that the increase in plasma lipids occurs via LXR-mediated induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program. .

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"V体育安卓版" Figures

Figure 1
Figure 1
Biochemical characterization of LXR ligands T0314407 and T0901317. (A) Chemical structure of T0314407, T0901317, and radiolabeled T0314407. (B) Effect of different LXRα agonists on recruitment of an LXXLL-containing peptide to the LXRα ligand-binding domain. (C) Scintillation proximity assay (SPA) data showing the competitive binding curves of [3H]-T0314407 to LXRα protein and the ability of unlabeled LXR ligands to displace [3H]-T0314407.
Figure 2
Figure 2
(A) Dose responses to LXR ligands in an HEK293 transient transfection assay using a wild-type LXRα expression plasmid and a luciferase reporter gene containing two copies of an LXR response element. DMSO treatments were used to derive the basal level of activation. (B) Specificity of LXR activation by LXR ligands in a transient transfection assay. HEK293 cells were cotransfected with a luciferase reporter gene containing four copies of the Gal4 DNA-binding site and the various chimeric Gal4 (DNA-binding domain)-nuclear receptor (ligand-binding domain) proteins shown. Cells were treated with the indicated compounds at concentrations of 1 μM, 5 μM, and 10 μM for T0901317, T0314407, and 24,25-EC, respectively.
Figure 3
Figure 3
Plasma lipid levels in animals treated with LXR agonist T0901317. The concentrations of (A) plasma triglycerides and (B) HDL-cholesterol for C57BL/6 mice (n = 5, for each treatment group; M, males; F, females). (C) Separation of Golden Syrian hamster plasma by fast protein liquid chromatography (FPLC) in combination with analysis of the triglyceride content across FPLC fractions. Lipid data are reported as the mean ± SD for the number of determinations (animals) described in each experiment. Statistical significance (kybd) was defined as P < 0.05 (ANOVA using SAS programming statistical test for controls and LXR agonist-treated animals).
Figure 4
Figure 4
Northern blot analysis. Total RNA was isolated from the tissues indicated from mice (A,B,C) and hamsters (D). The numerical data shown with each figure represents the fold increase (+) or decrease (−) of expression relative to corresponding vehicle-treated controls. (E) HepG2 cells were incubated in culture media with or without cycloheximide (cyclohex).
Figure 5
Figure 5
Agonist T0901317-mediated increases in hepatic and plasma triglyceride levels and lipogenic mRNA requires LXRs. Analysis of the lipid content of livers and plasma from vehicle- and T0901317-treated wild-type and LXRα/β−/− mice (n = 5 for each of the four groups shown, treatment for 7 d). Pooled plasma (50 μL from each of five mice per group) was fractionated and lipids analyzed as described. Shown are the concentrations for (A) FPLC triglyceride, (B) FPLC phospholipid, and (C) hepatic triglyceride. (D) Northern blot analysis of hepatic SREBP-1, SREBP-2, SCD-1, FAS, and ACC mRNA levels.
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