Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

Jun Zhang,Min Huang,Yijuan Wei,Bingfang Hu,Wen Xie,Yonggong Zhai,Makoto Makishima

doi:10.1371/journal.pone.0067959

Jun Zhang, Min Huang + Show 5 more

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https://doi.org/10.1371/journal.pone.0067959

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Abstract

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene.

Highlights

Lipid homeostasis is tightly maintained by balanced lipogenesis, catabolism (b-oxidation), and uptake/secretion
liver X receptors (LXRs) form a heterodimer with retinoid X receptor (RXR) and bind to its direct target lipogenic genes promoter, such as fatty acid synthase (FAS), or up-regulate the sterol regulatory element binding protein (SREBP)-1c, a transcriptional factor known to regulate the expression of a battery of lipogenic enzymes [5,6,7]
The Expression of stearoyl-CoA desaturase-1 (SCD1) was Induced in HepG2-pregnane X receptor (PXR) Cells We examined the expression of genes involved in lipid homeostasis in HepG2-PXR and HepG2-Vector cells with or without rifampicin incubation

Summary

Introduction

Lipid homeostasis is tightly maintained by balanced lipogenesis, catabolism (b-oxidation), and uptake/secretion. Several nuclear receptors have been implicated in lipid homeostasis, such as the liver X receptors (LXRs) [1], thyroid hormone receptor (TR) [2] and peroxisome proliferator-activated receptors (PPARs). Both LXRa and LXRb have been shown to promote lipogenesis though direct and indirect mechanism [1,3,4]. LXRs form a heterodimer with retinoid X receptor (RXR) and bind to its direct target lipogenic genes promoter, such as FAS, or up-regulate the sterol regulatory element binding protein (SREBP)-1c, a transcriptional factor known to regulate the expression of a battery of lipogenic enzymes [5,6,7]. While expression of an activated form of PPARd in the adipose tissues of transgenic mice was shown to activate fat metabolism and produce lean mice that are resistant to obesity induced either genetically or by a high fat diet [18]

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