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SHR Neuro Krebs Kardio Lipid

Bitter, A; Rümmele, P; Klein, K; Kandel, BA; Rieger, JK; Nüssler, AK; Zanger, UM; Trauner, M; Schwab, M; Burk, O.
Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms.
Arch Toxicol. 2015; 89(11):2089-2103
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Autor/innen der Med Uni Graz:
Trauner Michael
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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.
Find related publications in this database (using NLM MeSH Indexing)
Acetyl-CoA Carboxylase - metabolism
Aldehyde Reductase - genetics
Fatty Liver - genetics
Fatty Liver - pathology
Gene Knockdown Techniques -
Gene Silencing -
Hep G2 Cells -
Hepatocytes - pathology
Humans -
Ligands -
Lipogenesis - genetics
Pregnane X Receptor -
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
Sterol Regulatory Element Binding Protein 1 - metabolism
Triglycerides - metabolism
Up-Regulation - genetics

Find related publications in this database (Keywords)
Lipogenesis
Nuclear receptors
Hepatocyte
Pregnane X receptor
Sterol regulatory element-binding protein 1
Non-alcoholic steatohepatitis
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