title: Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms.
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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bitter
authors.affiliation: Institute of Pathology, University of Regensburg, Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Kandel
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Rieger
authors.affiliation: Department of Traumatology, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.|Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany. oliver.burk@ikp-stuttgart.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000449:Aldehyde Reductase / Q000235:genetics; D000074408:Aldo-Keto Reductases; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008024:Ligands; D050155:Lipogenesis / Q000235:genetics; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D000103:Acetyl-CoA Carboxylase
keywords: Hepatocyte; Lipogenesis; Non-alcoholic steatohepatitis; Nuclear receptors; Pregnane X receptor; Sterol regulatory element-binding protein 1