Background and Purpose: Diethyldithiocarbamate(DDC) alleviates hepatic inflammation and fibrosis of methionine- and choline-deficient(MCD) diet-induced non-alcoholic steatohepatitis(NASH) in mice. Interestingly, increased macrovesicular steatosis replace the ballooning of hepatocytes by DDC. The therapeutic mechanism of DDC on NASH remains unclear. Experimental Approach: C57BL/6 mice received choline-deficient, L-amino acid-defined(CDAA) diet to induce NASH with or without DDC treatment. Lipidomic and microarray analyses were used to find the lipid metabolites and genes regulated by DDC. RNAscope and immunoblotting were used to detect perilipin 5(Plin5) in the liver. Peridroplet mitochondria(PDM) were isolated from liver tissues, stained and observed by confocal microscope. Mixture of Oleic and palmitic acid were used to treat C3A cells. The effect of DDC on Plin5, mitochondria-LD contact and mitochondrial function were analyzed. Key Results: DDC alleviated hepatic inflammation and fibrosis, whereas steatosis increased in CDAA-diet induced NASH. Triglyceride content and genes related to LDs and mitochondrial function increased by DDC. Plin5 which can promote the expansion of LD and formation of PDM was upregulated in the liver by DDC. PDM were observed in steatotic liver and have enhanced mitochondrial function relative to cytoplasm mitochondria. DDC increased the size of LDs and the number of PDM, and improved mitochondrial function both in vivo and in vitro. Conclusion and Implications: PDM promote triglyceride synthesis and reduce lipotoxicity-induced liver injury, inflammation and fibrosis. PDM regulated by Plin5 contribute to the therapeutic effect of DDC on NASH. The regulation of PDM may represent an attractive pharmacological target for NAFLD.

Objective: To develop a novel non-invasive model for CSPH, and investigate whether carvedilol could reduce the risk of decompensation in patients with high-risk CSPH stratified by the novel model. Methods: International multicenter observational study with a median follow-up time of 38 months. Three cohorts were included in study from 6 countries. In this study, a total of 1,304 patients were fulfilled diagnosis of liver cirrhosis. Patients were treated with carvedilol in longitudinal carvedilol-treating cohort. The primary outcome was the development of the first hepatic decompensation . Results: Six studies from the meta-analysis were involved (n=819), and LSM and platelet count (PLT) were identified as independent risk factors of CSPH, with pooled risk ratios of 1.10 (95% confidence interval [CI] 1.06-1.15) and 0.99 (95% CI 0.98-0.99). A novel model was established. In HVPG cohort (n=151), the areas under the receiver operating characteristic curve (AUC) of the novel model, ANTICIPATE model, and Baveno VII criteria for CSPH were 0.91 (95% CI 0.86-0.95), 0.80 (95% CI 0.73-0.87), and 0.83 (95% CI 0.77-0.89). The novel model narrows down the grey zone to 22.5%, significantly lower than 50.3%, using Baveno VII criteria (p<0.001). In follow-up cohort (n=1,102), the cumulative incidences (1.7% vs 2.5% vs 15.8%) of decompensation events were significantly different by using the novel model cutoff values of >0, 0 to -0.68 (medium-risk), and <-0.68 (p<0.001). In the carvedilol-treating cohort, the patients with high-risk CSPH stratified by the novel model (treating cohort, n=51) had significantly lower rates of decompensation than those of NSBBs untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=102 after PSM, all p<0.05). Conclusion: A novel model provides stratification for CSPH and decompensation in patients with liver cirrhosis. Treatment with carvedilol significantly reduces the risk of decompensation among high-risk CSPH patients stratified by the novel model.