Genipin Reverses HFD-Induced Liver Damage and Inhibits UCP2-Mediated Pyroptosis in Mice

Abstract

Background/Aims: Liver damage is a typical manifestation of nonalcoholic fatty liver disease (NAFLD). It originates from excessive fat accumulation, leading to hepatocyte death, inflammation, and fibrosis. Nonalcoholic steatohepatitis (NASH) is a type of NAFLD with a prevalence of 49% in morbidly obese patients. Pyroptosis plays an important role in the development of NASH; thus, it is important to elucidate the effect of lipid accumulation on pyroptosis. Genipin (GNP), a natural water-soluble cross-linking agent, has hepatoprotective effects and decreases lipid accumulation in the liver; however, the mechanisms underlying these effects are unknown. Methods: In this study, qPCR and Western blot were used to examine pyroptotic gene expression in high-fat diet (HFD) induced obese mice and free fatty acids (FFAs) treated hepatocytes. At the same time, relative lactate dehydrogenase (LDH) release and Hoechst & propidium iodide (PI) staining were done to verify cell death. To explore the molecular mechanism, cell transfection were constructed with siRNA or plasmid to obtain knockdown or overexpression hepatocytes. Results: We found that HFD-fed mice and FFAs-treated hepatocytes had obvious pyroptosis, and addition of GNP reversed liver damage and inhibited pyroptosis both in vitro and in vivo. Besides, UCP2 knockdown cells showed suppressed FFAs-mediated pyroptosis, as determined by decreased pyroptotic gene expression, reduced lactate dehydrogenase (LDH) release, and reduced cell death. Consistent with this, cells transfected with UCP2 had upregulated pyroptotic gene expression, increased LDH release, and increased cell death. Conclusion: GNP reverses HFD-induced liver damage and inhibits UCP2-mediated pyroptosis. Thus, GNP may serve as a potential therapeutic candidate for NAFLD.

Deletion of mitochondrial uncoupling protein 2 exacerbates mitophagy and cell apoptosis after cerebral ischemia and reperfusion injury in mice

“…It has been reported that UCP2 reduces the ROS formation by preventing mitochondrial membrane hyperpolarization that in turn inhibits mitochondrial electron transport chain. Studies have shown that UCP2 confers protective effects on various stressors by decreasing mitochondrial ROS production in the brain and cardiomyocytes [26][27][28][29]. MnSOD is encoded by nuclear genome, synthesized in the cytosol, transported into the mitochondrial matrix post translationally via TOM and TIM23 complexes, and assembled into active enzyme with the incorporation of a manganese ion in the mitochondrial matrix.…”

Deletion of Mitochondrial Uncoupling Protein 2 Exacerbates Mitochondrial Damage in Mice Subjected to Cerebral Ischemia and Reperfusion Injury under both Normo- and Hyperglycemic Conditions

“…UCP2 reduces the ROS formation by preventing mitochondrial membrane hyperpolarization that in turn inhibits mitochondrial electron transport chain. Studies have shown that UCP2 confers protective effects on various stressors by decreasing mitochondrial ROS production in the brain and liver 35 , 36 , 37 . It has also been reported that UCP2 could protect cardiomyocytes from exogenous oxidant stress 38 .…”

Genipin improves reproductive health problems caused by circadian disruption in male mice

“…Furthermore, GNP shows the choleretic effect by enhancing bilirubin disposal and augment of genes in charge of the efflux of a number of organic anions [ 45 ]. GNP widely implicates in the inhibition of uncoupling protein 2 (UCP2) in various experimental models of ROS generation [ 45 – 47 ]. This study demonstrated the protective effect of GNP against circadian disruption-induced damage of spermatogenesis and fertility in male mice.…”