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Liver X receptor (LXR) regulates human adipocyte lipolysis.

ABSTRACT: The Liver X receptor (LXR) is an important regulator of carbohydrate and lipid metabolism in humans and mice. We have recently shown that activation of LXR regulates cellular fuel utilization in adipocytes. In contrast, the role of LXR in human adipocyte lipolysis, the major function of human white fat cells, is not clear. In the present study, we stimulated in vitro differentiated human and murine adipocytes with the LXR agonist GW3965 and observed an increase in basal lipolysis. Microarray analysis of human adipocyte mRNA following LXR activation revealed an altered gene expression of several lipolysis-regulating proteins, which was also confirmed by quantitative real-time PCR. We show that expression and intracellular localization of perilipin1 (PLIN1) and hormone-sensitive lipase (HSL) are affected by GW3965. Although LXR activation does not influence phosphorylation status of HSL, HSL activity is required for the lipolytic effect of GW3965. This effect is abolished by PLIN1 knockdown. In addition, we demonstrate that upon activation, LXR binds to the proximal regions of the PLIN1 and HSL promoters. By selective knock-down of either LXR isoform, we show that LXRα is the major isoform mediating the lipolysis-related effects of LXR. In conclusion, the present study demonstrates that activation of LXRα up-regulates basal human adipocyte lipolysis. This is at least partially mediated through LXR binding to the PLIN1 promoter and down-regulation of PLIN1 expression.

SUBMITTER: Stenson BM

PROVIDER: S-EPMC3012995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims/introductionHigh glucose increases the accumulation of lipid droplets in hepatocytes, which eventually results in nonalcoholic fatty liver disease in patients with diabetes. However, the specific mechanism or communication between adipocyte and hepatocyte lipid metabolism is still ambiguous.Materials and methodsIn this study, exosomes released from human adipocytes were isolated and identified by their morphology, size, and marker proteins by using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting (WB). Gene expression was detected by qRT-PCR and WB. Lipid accumulation was determined by oil red O staining and analyses of total cholesterol (TC) and triglyceride (TG) content.ResultsOur results showed that co-culture of HepG2 cells with adipocytes under high glucose conditions stimulated lipid deposition and LINC01705 expression in the HepG2 cells. Exosomes extracted from adipocytes cultured under high glucose conditions had higher levels of LINC01705 than exosomes extracted from adipocytes cultured under normal glucose conditions. Moreover, LINC01705 expression was also elevated in exosomes extracted from diabetes patients when compared with exosomes isolated from normal volunteers, and exosomes from patients who had diabetes complicated with fatty liver (DCFL) had the highest levels of LINC01705 expression. Treatment of HepG2 cells with exosomes extracted from high glucose-stimulated adipocytes promoted lipid deposition and LINC01705 expression in HepG2 cells. Further experiments showed that overexpression of LINC01705 promoted HepG2 lipid metabolism, while inhibition of LINC01705 had the opposite effect. Mechanistically, LINC01705 competitively bound to miR-552-3p, and treatment with miR-552-3p inhibitor reversed the effects induced by LINC01705 knockdown. Moreover, miR-552-3p was found to regulate the transcription activity of LXRα and thereby modulate lipid metabolism-related gene expression.ConclusionsWhen taken together, our findings showed that high glucose increased the LINC01705 levels in adipocyte exosomes, and thereby improved HepG2 lipid accumulation via an miR-552-3p/LXR axis.

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Liver X receptor (LXR) regulates human adipocyte lipolysis.

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