The impact of pregnane X receptor activation on liver fibrosis

2006 ◽  
Vol 34 (6) ◽  
pp. 1119-1123 ◽  
Author(s):  
M.C. Wright
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
Nuclear Receptor ◽  
Hepatic Stellate Cells ◽  
Pregnane X Receptor ◽  
Stellate Cells ◽  
Receptor Activation ◽  
Additional Function ◽  
Expression Of Genes ◽  
The Impact

The PXR (pregnane X receptor) is a nuclear receptor transcription factor that is activated by a range of endobiotics and xenobiotics. The activated PXR modulates the transcription of genes in hepatocytes (the main functional cell of the liver) associated with endobiotic and xenobiotic uptake, metabolism and excretion. However, activation of the PXR also inhibits a deleterious response of the liver to chronic damage – that of fibrosis. The antifibrogenic mode of action is mediated through changes in the expression of genes in hepatic stellate cells and liver macrophages (Kupffers). These results suggest an additional function for the PXR.

The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis

2004 ◽  
Vol 127 (5) ◽  
pp. 1497-1512 ◽  
Author(s):  
Stefano Fiorucci ◽  
Elisabetta Antonelli ◽  
Giovanni Rizzo ◽  
Barbara Renga ◽  
Andrea Mencarelli ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Nuclear Receptor ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Curcumin Protects Hepatic Stellate Cells against Leptin-Induced Activation in Vitro by Accumulating Intracellular Lipids

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4168-4177 ◽  
Author(s):  
Youcai Tang ◽  
Anping Chen
Keyword(s):  
Hepatic Stellate Cells ◽  
Lipid Accumulation ◽  
Stellate Cells ◽  
Type Ii Diabetes Mellitus ◽  
Intracellular Lipids ◽  
Expression Of Genes ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase ◽  
The Impact

Obesity and type II diabetes mellitus are often associated with hyperleptinemia and commonly accompanied by nonalcoholic steatohepatitis, which could cause hepatic fibrosis. During hepatic fibrogenesis, the major effectors hepatic stellate cells (HSCs) become active, coupling with depletion of cellular lipid droplets and downexpression of genes relevant to lipid accumulation. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit HSC activation. We recently reported that leptin stimulated HSC activation, which was eliminated by curcumin, a phytochemical from turmeric. The current study was designed to explore the underlying mechanisms, focusing on their effects on the level of intracellular lipids. We hypothesized that one of the mechanisms by which leptin stimulated HSC activation was to stimulate the depletion of intracellular lipids, which could be abrogated by curcumin by inducing expression of genes relevant to lipid accumulation. In this report, we observed that leptin dose dependently reduced levels of intracellular fatty acids and triglycerides in passaged HSCs, which were eliminated by curcumin. The phytochemical abrogated the impact of leptin on inhibiting the activity of AMP-activated protein kinase (AMPK) in HSCs in vitro. The activation of AMPK resulted in inducing expression of genes relevant to lipid accumulation and increasing intracellular lipids in HSCs in vitro. In summary, curcumin eliminated stimulatory effects of leptin on HSC activation and increased AMPK activity, leading to inducing expression of genes relevant to lipid accumulation and elevating the level of intracellular lipids. These results provide novel insights into mechanisms of curcumin in inhibiting leptin-induced HSC activation.

scholarly journals Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Lina Sun ◽  
Zhiwen Fan ◽  
Junliang Chen ◽  
Wenfang Tian ◽  
Min Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
High Glucose ◽  
Interstitial Fibrosis ◽  
Stellate Cells ◽  
Quiescent State ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Sirt1 Expression ◽  
Primary Mouse

Abstract Interstitial fibrosis represents a key pathological process in non-alcoholic steatohepatitis (NASH). In the liver, fibrogenesis is primarily mediated by activated hepatic stellate cells (HSCs) transitioning from a quiescent state in response to a host of stimuli. The molecular mechanism underlying HSC activation is not completely understood. Here we report that there was a simultaneous up-regulation of PIAS4 expression and down-regulation of SIRT1 expression accompanying increased hepatic fibrogenesis in an MCD-diet induced mouse model of NASH. In cultured primary mouse HSCs, stimulation with high glucose activated PIAS4 while at the same time repressed SIRT1. Over-expression of PIAS4 directly repressed SIRT1 promoter activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HSCs treated with high glucose. Estrogen, a known NASH-protective hormone, antagonized HSC activation by targeting PIAS4. Lentivirus-mediated delivery of short hairpin RNA (shRNA) targeting PIAS4 in mice ameliorated MCD diet induced liver fibrosis by normalizing SIRT1 expression in vivo. PIAS4 promoted HSC activation in a SIRT1-dependent manner in vitro. Mechanistically, PIAS4 mediated SIRT1 repression led to SMAD3 hyperacetylation and enhanced SMAD3 binding to fibrogenic gene promoters. Taken together, our data suggest SIRT1 trans-repression by PIAS4 plays an important role in HSC activation and liver fibrosis.

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