Methods: Fifty-one genes, which are associated with retinoid metabolism and action, were examined in thirty six subjects including 17 patients with simple steatosis,
11 with non-alcoholic steatohepatitis (NASH) and eight controls were examined by real-time reverse transcriptase polymerase chain reaction. Immunohistochemical study was also done by 3 kinds of antibodies. Results: Higher expression of CRBP1 LRAT, DGT1/2 and CES1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively. Expression of ADH1/2/3, RDH5/10/11, DHRS3 and RALDH1/3 was increased in NAFLD, suggesting that oxidation process from retinol to all-trans retinoic acid (ATRA) was enhanced. Importantly, greater expression of CYP26A1 indicated that degradation
of ATRA was enhanced in NAFLD. Further, expression of SOD1/2, catalase, thioredoxin and uncoupling protein 2 was see more also enhanced. Conclusion: Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD, which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC. “
“Inflammasome activation has been recently recognized to play a central role in the development of drug-induced and obesityassociated liver disease. However, the sources and mechanisms of inflammasome mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. Methods: We generated global and myeloid cell specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 medchemexpress mutation
check details (ortholog of D303N in human NLRP3) resulting in a constitutively activated NLRP3. To study the presence and significance of NLRP3 initiated pyroptotic cell death, we separated hepatocytes from non-parenchymal cells and developed a novel flow cytometry-based (FAGS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase1 (Gasp1) and propidium iodide (PI) positive cells. Liver inflammation was quantified histologically, by FACS and via gene expression analysis. Liver fibrosis was assessed by morphometric quantitation of Sirius-Red-staining and qPGR for markers of hepatic stellate cell-(HSG)-activation. Results: NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC-activation. Nlrp3 global mutants showed increased collagen deposition, visualized by Sirius red staining in close proximity to inflammatory hot spots and displayed significantly higher connective tissue growth factor (CTGF) and tissue inhibitor of matrix metalloproteinase 1(TIMP1) mRNA levels compared to WT mice. Inflammation and HSC-activation were partially attenuated by treatment with anakinra, an interleukin1 receptor antagonist.