Diethyldithiocarbamate inhibits the activation of hepatic stellate cells via PPAR?/FABP1 in mice with non-alcoholic steatohepatitis

Activation of hepatic stellate cells (HSCs) is the main course of liver fibrosis which is positively correlated with adverse clinical outcomes in non-alcoholic steatohepatitis (NASH). Diethyldithiocarbamate (DDC) attenuates NASH related liver fibrosis in mice, but its underlying mechanisms remains unclear. In this study, the data showed that DDC inhibited the activation of HSCs in high fat choline-deficient, L-amino acid-defined (CDAA) diet induced NASH. Double Immunofluorescence analysis showed that the baseline expression of peroxisome proliferator-activated receptor a (PPARa) is high in HSCs in normal mouse liver and notably decreases in the NASH liver, indicating that PPARa might be associated with the activation of HSCs. While, DDC upregulated PPARa in HSCs in the NASH liver. Mixture of free fatty acid was used to induce steatosis of hepatocytes. Human HSCs (LX-2 cells) were activated after co-cultured with steatotic hepatocytes, and DDC inhibited the activation of LX-2 cells. Meanwhile, DDC upregulated PPARa and FABP1, and promoted the accumulation of LDs in LX-2 cells. PPARa small interfering RNA blocked these effect of DDC. These findings suggest that PPARa is associated with the activation of HSCs in the context of NASH. DDC improves NASH related fibrosis through inhibiting the activation of HSCs via PPARa/FABP1.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis in non-alcoholic steatohepatitis (NASH). Diethyldithiocarbamate (DDC) inhibits the activation of HSCs in NASH through the PPARa pathway.