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

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.

Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

“…In addition, hepatic Scd-1 was rapidly up-regulated by rifampicin. These results are in agreement with an in vitro report, in which SCD-1 and long chain free fatty acid elongase were up-regulated in rifampicin-treated HepG2 cells [19]. These results suggest that rifampicin-induced hepatic lipid accumulation is partially attributed to the increased hepatic lipid synthesis.…”

The constitutive androstane receptor and pregnane X receptor in the brain

“…Furthermore, the ligand-based activation of NR1I3 decreases the expression of carnitine palmitoyltransferase 1 (CPT1A), an enzyme involved in mitochondrial β-oxidation of fatty acids and the ketogenic enzyme 3-hydroxymethylglutaryl CoA synthase 2 (HMGCS2) (Gao et al, 2009). Conversely, NR1I2 exerts an inductive effect on lipogenesis through up-regulation of SCD-1 (Nakamura et al, 2007;Zhang et al, 2013), the fatty acid transporter CD36 (Zhou et al, 2008) and…”

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome

“…Activation of mouse PXR in liver leads to increased deposit of triglycerides in liver, and this is associated with increased expression of the free fatty acid transporter CD36, which is a direct PXR-target gene (Zhou et al, 2006; Zhou et al, 2008). Activation of human PXR in HepG2 cells promotes lipid synthesis, and this is associated with increased expression of stearoyl-CoA desaturase-1 (SCD1), which is a direct PXR-target gene (Zhang et al, 2013). Chronic exposure to rifaximin causes hepatic steatosis in PXR-humanized mice (Cheng et al, 2012); PXR-humanized mice fed a high-fat diet gain more body weight, exhibit hyperinsulinemia, and impaired glucose tolerance (Spruiell et al, 2014); whereas PXR depletion alleviates diet-induced and genetic obesity as well as insulin resistance in mice (He et al, 2013).…”