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

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgments

We appreciate the expert technical assistance of K. Abuazi-Rincones. The nonprofit foundation Human Tissue and Cell Research (Regensburg, Germany) kindly provided human hepatocytes from four additional donors. This work contains parts of the doctoral thesis of A.B. It was supported, in whole or in part, by the Robert Bosch Foundation, Stuttgart, Germany, by the Interfaculty Center for Pharmacogenomics and Drug Research of the University of Tübingen, Germany, Grant 3-0-0 (to O.B.), by the German Federal Ministry of Education and Research, HepatoSys Grants 0313080I (to O.B.) and 0313081B (to A.K.N.) and Virtual Liver Network Grant 0315755 (to U.M.Z., and M.S.), and by Grant F3008 from the Austrian Science Foundation (to M.T.).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

Liver resections of tumor patients, which were used for the preparation of primary human hepatocytes, were performed according to the respective institutional guidelines including the patient’s written informed consent, which were approved by the local ethical committee of the Charité, Humboldt University Berlin, Germany. The human liver biobank study was approved by the local ethical committees of the Charité, Humboldt University, Berlin, and University of Tübingen and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient.

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Andreas Bitter, Kathrin Klein, Benjamin A. Kandel, Jessica K. Rieger, Ulrich M. Zanger, Matthias Schwab & Oliver Burk

  2. Institute of Pathology, University of Regensburg, Regensburg, Germany

    Petra Rümmele

  3. Department of Traumatology, University of Tübingen, Tübingen, Germany

    Andreas K. Nüssler

  4. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Michael Trauner

  5. Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany

    Matthias Schwab

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  1. Andreas Bitter
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Correspondence to Oliver Burk.

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Bitter, A., Rümmele, P., Klein, K. et al. Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. Arch Toxicol 89, 2089–2103 (2015). https://doi.org/10.1007/s00204-014-1348-x

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