Liver fibrosis/cirrhosis is significant health burden worldwide, resulting in liver failure or cancer and accounting for many deaths each year. The pathogenesis of liver fibrosis is very complex, which makes treatment challenging. Growth differentiation factor 15 (GDF15), a cysteine knot protein belonging to the transforming growth factor β (TGF-β) superfamily, has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. However, paucity of literature is available about GDF15 function in liver fibrosis. This study aimed to investigate the immunomodulatory role and therapeutic potential of GDF15 in progression of hepatic fibrosis. GDF15 expression was studied in patients with fibrosis/cirrhosis and in 2 murine models of liver fibrosis, including mice treated with CCl₄ or DDC diet. GDF15 involvement in the pathogenesis of liver fibrosis was assessed in Gdf15 knockout mouse using both CCl₄ and DDC diet experimental models. We used the CCl₄ and/or DDC diet-induced liver fibrosis model to examine the antifibrotic and anti-inflammatory effects of AAV8-mediated GDF15 overexpression in hepatocytes or recombinant mouse GDF15. GDF15 expression is decreased in the liver of animal models and patients with liver fibrosis/cirrhosis compared with those without liver disease. In vivo studies showed that GDF15 deficiency aggravated CCl₄ and DDC diet-induced liver fibrosis, while GDF15 overexpression mediated by AAV8 or its recombinant protein alleviated CCl₄ and/or DDC diet-induced liver fibrosis. In Gdf15 knockout mice, the intrahepatic microenvironment that developed during fibrosis showed relatively more inflammation, as demonstrated by enhanced infiltration of monocytes and neutrophils and increased expression of proinflammatory factors, which could be diminished by AAV8-mediated GDF15 overexpression in hepatocytes. Intriguingly, GDF15 exerts its effects by reprogramming the metabolic pathways of macrophages to acquire an oxidative phosphorylation-dependent anti-inflammatory functional fate. Furthermore, adoptive transfer of GDF15-preprogrammed macrophages to mouse models of liver fibrosis induced by CCl₄ attenuated inflammation and alleviated the progression of liver fibrosis. GDF15 ameliorates liver fibrosis via modulation of liver macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest that GDF15 is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD), as one of the main causes of chronic liver disease worldwide, encompasses a spectrum of liver conditions that are not caused by other etiology, such as overt alcohol consumption, from simple steatosis to more aggressive non-alcoholic steatohepatitis (NASH) that involves liver inflammation and fibrosis, and to the lethal cirrhosis that may result in liver cancer and liver failure. The molecular mechanisms governing the transition from steatosis to NASH remain not fully understood, but the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis, which also correlate with disease progression. With the tremendous advancement in the field of lipidomics in last two decades, a better understanding of the specific role of sphingolipids in fatty liver disease has taken shape. Among the numerous lipid subtypes that accumulate, ceramides are particularly impactful. On the one hand, excessive ceramides deposition in the liver cause hepatic steatosis. On the other hand, ceramides as lipotoxic lipid have significant effects on hepatic inflammation, apoptosis and insulin resistance that contribute to NAFLD. In this review, we summarize and evaluate current understanding of the multiple roles of ceramides in the onset of fatty liver disease and the pathogenic mechanisms underlying their effects, and we also discuss recent advances and challenges in pharmacological interventions targeting ceramide metabolism for the treatment of NAFLD.

Objectives: Tocilizumab (TCZ) is the only available biologics inhibiting interleukin-6 presently, and emerging evidences have figured that elevated serum level of interleukin-6 is a crucial link of the pathogenesis of adult-onset Still’s disease (AOSD). However, evidence about the efficacy and safety of TCZ in AOSD with strong power is still scarce. Thus, this meta-analysis was conducted to synthetically assess the efficacy and safety of TCZ on AOSD. Methods: PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Chinese Biological Medical Literature database were comprehensively searched up to 31 July 2017 for the pertinent studies. The pooled remission rates were synthesized by fixed effect model or randomized effects model, depended on heterogeneity. Results: Ten original studies contained 147 individuals were included in our analysis. The overall partial and complete remission rates were 85.38 (95% CI: 69.32–96.88%) and 77.91% (95% CI: 57.91–90.04%), respectively, and the remission rate of refractory patients was 87.92% (95% CI: 56.53–100.00%). Conclusion: The use of TCZ could significantly reduce the need of corticosteroids for AOSD patients. Impressive improvements were attained in both clinical and laboratory parameters. Compared with conventional therapy, TCZ treatment was safety. In conclusion, TCZ was effective and well tolerated for the treatment of AOSD.