Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.4.1.2 (
acetyl-CoA carboxylase
)
2,876
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. 2518 22
