Merck
  • Home
  • Search Results
  • Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms.

Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms.

Archives of toxicology (2014-09-04)
Andreas Bitter, Petra Rümmele, Kathrin Klein, Benjamin A Kandel, Jessica K Rieger, Andreas K Nüssler, Ulrich M Zanger, Michael Trauner, Matthias Schwab, Oliver Burk
ABSTRACT

In addition to its well-characterized role in the regulation of drug metabolism and transport by xenobiotics, pregnane X receptor (PXR) critically impacts on lipid homeostasis. In mice, both ligand-dependent activation and knockout of PXR were previously shown to promote hepatic steatosis. To elucidate the respective pathways in human liver, we generated clones of human hepatoma HepG2 cells exhibiting different PXR protein levels, and analyzed effects of PXR activation and knockdown on steatosis and expression of lipogenic genes. Ligand-dependent activation as well as knockdown of PXR resulted in increased steatosis in HepG2 cells. Activation of PXR induced the sterol regulatory element-binding protein (SREBP) 1-dependent lipogenic pathway via PXR-dependent induction of SREBP1a, which was confirmed in primary human hepatocytes. Inhibiting SREBP1 activity by blocking the cleavage-dependent maturation of SREBP1 protein impaired the induction of lipogenic SREBP1 target genes and triglyceride accumulation by PXR activation. On the other hand, PXR knockdown resulted in up-regulation of aldo-keto reductase (AKR) 1B10, which enhanced the acetyl-CoA carboxylase (ACC)-catalyzed reaction step of de novo lipogenesis. In a cohort of human liver samples histologically classified for non-alcoholic fatty liver disease, AKR1B10, SREBP1a and SREBP1 lipogenic target genes proved to be up-regulated in steatohepatitis, while PXR protein was reduced. In summary, our data suggest that activation and knockdown of PXR in human hepatic cells promote de novo lipogenesis and steatosis by induction of the SREBP1 pathway and AKR1B10-mediated increase of ACC activity, respectively, thus providing mechanistic explanations for a putative dual role of PXR in the pathogenesis of steatohepatitis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
二甲基亚砜, Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
Sigma-Aldrich
二甲基亚砜, anhydrous, ≥99.9%
Sigma-Aldrich
二甲基亚砜, for molecular biology
Sigma-Aldrich
水, Nuclease-Free Water, for Molecular Biology
Sigma-Aldrich
二甲基亚砜, ACS reagent, ≥99.9%
Sigma-Aldrich
二甲基亚砜, sterile-filtered, BioPerformance Certified, meets EP, USP testing specifications, suitable for hybridoma
Sigma-Aldrich
水, sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
甲醛 溶液, ACS reagent, 37 wt. % in H2O, contains 10-15% Methanol as stabilizer (to prevent polymerization)
Sigma-Aldrich
二甲基亚砜, ReagentPlus®, ≥99.5%
Sigma-Aldrich
二甲基亚砜, ≥99.5% (GC), suitable for plant cell culture
Sigma-Aldrich
甲醛 溶液, for molecular biology, 36.5-38% in H2O
Sigma-Aldrich
利福平, ≥97% (HPLC), powder
Sigma-Aldrich
水, deionized
Sigma-Aldrich
水, for molecular biology, sterile filtered
Sigma-Aldrich
二甲基亚砜, meets EP testing specifications, meets USP testing specifications
Sigma-Aldrich
二甲基亚砜, puriss. p.a., ACS reagent, ≥99.9% (GC)
Sigma-Aldrich
水, for embryo transfer, sterile-filtered, BioXtra, suitable for mouse embryo cell culture
Sigma-Aldrich
甲醛 溶液, for molecular biology, BioReagent, ≥36.0% in H2O (T)
Supelco
双酚 A, ≥99%
SAFC
甲醛 溶液, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
Sigma-Aldrich
二甲基亚砜, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
二甲基亚砜, PCR Reagent
Sigma-Aldrich
水, BioPerformance Certified
Sigma-Aldrich
DL-萝卜硫素, ≥90% (HPLC), synthetic, liquid
Sigma-Aldrich
水, for cell biology, sterile ultrafiltered
Sigma-Aldrich
甲醛 溶液, meets analytical specification of USP, ≥34.5 wt. %
Sigma-Aldrich
二甲基亚砜 溶液, 50 wt. % in H2O
Supelco
甲醛 溶液, stabilized with methanol, ~37 wt. % in H2O, certified reference material
Sigma-Aldrich
水, PCR Reagent