The platelet-derived growth factor (PDFG) signaling pathway exerts persistent activation in response to a variety of stimuli and facilitates the progression of hepatic fibrosis. Since this pathway modulates a broad spectrum of cellular processes, including cell growth, differentiation, inflammation and carcinogenesis, it has emerged as a therapeutic target for hepatic fibrosis and liver-associated disorders. The present review exhibits the current knowledge of the role of the PDGF signaling pathway and its pathological profiles in hepatic fibrosis, and assesses the potential of inhibitors which have been investigated in the experimental hepatic fibrosis model, in addition to the clinical challenges associated with these inhibitors.

Lipotoxicity induced by saturated fatty acids (SFAs) plays a pathological role in the development of non-alcoholic fatty liver disease (NAFLD); however, the exact mechanism remains to be clearly elucidated. Palmitate is the most abundant SFA in the circulation and major lipotoxic inducer. Accumulating evidence supports that autophagy induction is protective against palmitate-induced cell death in a variety of cell types, including hepatocytes. Nicotinamide is the amide form of nicotinic acid (vitamin B3, Niacin) and a dietary supplementation as a source of vitamin B3. We previously reported that nicotinamide endowed hepatocytes resistance to palmitate-induced ER stress via upregulating SIRT1, with cAMP/PKA/CREB pathway activation being a fundamental mechanism. This study was undertaken to investigate the potential anti-lipotoxic effect of nicotinamide and to elucidate underlying mechanism(s). Our data demonstrated that nicotinamide supplementation protected hepatocytes against palmitate-induced cell death. Mechanistic investigations revealed that nicotinamide supplementation activated autophagy in hepatocytes. Importantly, we showed that the anti-lipotoxic property of nicotinamide was abolished by autophagy inhibitors, suggesting that autophagy induction plays a mechanistic role in nicotinamide's anti-lipotoxic effect. Furthermore, we showed that SIRT1 inhibition blunted autophagy induction in response to nicotinamide supplementation and similarly abrogated the anti-lipotoxic effect conferred by nicotinamide supplementation. In conclusion, our data suggest that nicotinamide protects against palmitate-induced hepatotoxicity via SIRT1-dependent autophagy induction and that nicotinamide supplementation may represent a therapeutic choice for NAFLD.

Background Alcoholic liver disease (ALD) is a type of chronic liver disease caused by chronic ethanol overconsumption. The pathogenesis of ALD is complex and there is no effective clinical treatment thus far. SIRT3 is an NAD + -dependent deacetylase primarily located inside mitochondria, and reports on the effect of chronic alcohol exposure on liver SIRT3 expression are scarce. This study aims to investigate the effect of chronic alcohol consumption on hepatic SIRT3 expression and its role in alcoholic-induced liver injury. Methods Using the Lieber-DeCarli mouse model of ALD, we analyzed the regulation of SIRT3 and the effect of liver-specific knocking-down of SIRT3 on alcohol-induced liver injury. HepG2 and AML12 hepatocytes were employed to detect the biological function of SIRT3 on alcohol-induced hepatic cytotoxicity and its potential mechanism. Results Chronic alcohol exposure led to hepatic SIRT3 upregulation and liver-specific SIRT3 knockdown alleviated alcoholic feeding-induced liver injury and lipid accumulation, which is associated with improved autophagy induction. In addition, autophagy induction contributed to the cytoprotective effect of SIRT3 knockdown on ethanol-induced hepatocyte cell death. Conclusion In summary, our data suggest that hepatic SIRT3 upregulation in response to chronic alcohol exposure and liver-specific SIRT3 knockdown, induced autophagy activation further alleviating alcoholic-induced liver injury, which represents a novel mechanism in this process.

Chronic kidney disease (CKD) has become a global healthcare issue. CKD can progress to irreversible end-stage renal diseases (ESRD) or renal failure. e major risk factors for CKD include obesity, diabetes, and cardiovascular diseases. Understanding the key process involved in the disease development may lead to novel interventive strategies, which is currently lagging behind. Peroxisome proliferator-activated receptor c (PPARc) is one of the ligand-activated transcription factor superfamily members and is globally expressed in human tissues. Its agonists such as thiazolidinediones (TZDs) have been applied as effective antidiabetic drugs as they control insulin sensitivity in multiple metabolic tissues. Besides, TZDs exert protective effects in multiple other CKD risk disease contexts. As PPARc is abundantly expressed in major kidney cells, its physiological roles in those cells have been studied in both cell and animal models. e function of PPARc in the kidney ranges from energy metabolism, cell proliferation to inflammatory suppression, although major renal side effects of existing agonists (including TZDs) have been reported, which limited their application in treating CKD. In the current review, we systemically assess the function of PPARc in CKDs and the benefits and current limitations of its agonists in the clinical applications.

Oxidative stress and TNFα are critically involved in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of dysregulated glutathione homeostasis, a principal feature of oxidative stress, on TNFα-induced hepatotoxicity and its mechanistic implications in NAFLD progression. We showed that mice fed a high-fat diet (HFD) for 12 weeks developed hepatic steatosis and liver injuries, which were associated with not only TNFα overproduction but also hepatic glutathione dysregulation, characterized by GSH reduction and GSSG elevation. Moreover, consuming a HFD increased protein S-glutathionylation (protein-SSG formation) in the liver. Subsequent cell culture studies revealed that GSSG accumulation, as opposed to GSH reduction, sensitized hepatocytes to TNFα killing by reducing the TNFα-triggered NF-κB activity. GSSG prevented TNFα-induced activation of IKK-β, an upstream kinase in the NF-κB signaling pathway, by inducing IKK-β glutathionylation (IKK-β-SSG formation). In animal studies, in comparison to a control diet, HFD consumption resulted in increased hepatic IKK-β-SSG formation, leading to suppressed IKK-β activation and subsequent NF-κB suppression. Furthermore, we found that HFD consumption also led to decreased hepatic expression of glutaredoxin, a key enzyme for de-glutathionylation. Similarly, CdCl2, a chemical inhibitor of glutaredoxin, sensitized hepatocytes to TNFα-mediated cytotoxicity. In conclusion, our data suggest that GSSG is a potent and clinically relevant sensitizer for TNFα-induced hepatotoxicity in NAFLD, which represents a potential therapeutic target for NAFLD.