Bitter, Andreas and Ruemmele, Petra and Klein, Kathrin and Kandel, Benjamin A. and Rieger, Jessica K. and Nuessler, Andreas K. and Zanger, Ulrich M. and Trauner, Michael and Schwab, Matthias and Burk, Oliver (2015) Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. ARCHIVES OF TOXICOLOGY, 89 (11). pp. 2089-2103. ISSN 0340-5761, 1432-0738
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FATTY LIVER-DISEASE; DRUG-METABOLIZING-ENZYMES; NUCLEAR RECEPTOR; NONALCOHOLIC STEATOHEPATITIS; TRANSCRIPTION FACTORS; MOLECULAR-MECHANISMS; THERAPEUTIC TARGETS; INSULIN-RESISTANCE; LIPID-METABOLISM; GENE-EXPRESSION; Lipogenesis; Nuclear receptors; Hepatocyte; Pregnane X receptor; Sterol regulatory element-binding protein 1; Non-alcoholic steatohepatitis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2019 08:52 |
| Last Modified: | 06 May 2019 08:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4522 |
Actions (login required)
 |
View Item |
