Abstract
Resolvin D1 (RvD1) was previously reported to relieve inflammation and liver damage in several liver diseases, but its potential role in liver fibrosis remains elusive. The aim of our study was to investigate the effects and underlying mechanisms of RvD1 in hepatic autophagy in liver fibrosis. In vivo, male C57BL/6 mice were intraperitoneally injected with 20% carbon tetrachloride (CCl4, 5 ml/kg) twice weekly for 6 weeks to establish liver fibrosis model. RvD1 (100 ng or 300 ng/mouse) was added daily in the last 2 weeks of the modeling period. In vitro, lipopolysaccharide (LPS)-activated LX-2 cells were co-treated with increasing concentrations (2.5–10 nM) of RvD1. The degree of liver injury was measured by detecting serum AST and ALT contents and H&E staining. Hepatic fibrosis was assessed by masson's trichrome staining and metavir scoring. The qRT-PCR, western blot, immunohistochemistry, and immunofluorescence were applied to liver tissues or LPS-activated LX-2 cells to explore the protective effects of RvD1 in liver fibrosis. Our findings reported that RvD1 significantly attenuated CCl4 induced liver injury and fibrosis by decreasing plasma AST and ALT levels, reducing collagen I and α-SMA accumulation and other pro-fibrotic genes (CTGF, TIMP-1 and Vimentin) expressions in mouse liver, restoring damaged histological architecture and improving hepatic fibrosis scores. In vitro, RvD1 also repressed the LPS induced LX-2 cells activation and proliferation. These significant improvements mainly attributed to the inhibiting effect of RvD1 on autophagy in the process of hepatic stellate cell (HSC) activation, as demonstrated by decreased ratio of LC3-II/I and elevated p62 after RvD1 treatment. In addition, using AZD5363 (an AKT inhibitor that activates autophagy) and AZD8055 (an mTOR inhibitor, another autophagy activator), we further verified that RvD1 suppressed autophagy-mediated HSC activation and alleviated CCl4 induced liver fibrosis partly through AKT/mTOR pathway. Overall, these results demonstrate that RvD1 treatment is expected to become a novel therapeutic strategy against liver fibrosis.
Highlights
Liver fibrosis is the final common pathological condition of chronic liver injury of various etiologies and closely associated with cirrhosis, liver failure, and hepatocellular carcinoma (Parola and Pinzani, 2019)
Resolvin D1 (RvD1) treatment effectively repaired the destruction of liver tissue structure and reduced collagen fiber hyperplasia (Figures 1E,G), the fibrosis scoring was correspondingly decreased according to pathophysiological evaluations (Figure 1F)
There was no significant difference observed in mice liver weight, the mice body weight returned concomitant with decreased liver index after RvD1 intervention (Table 1)
Summary
Liver fibrosis is the final common pathological condition of chronic liver injury of various etiologies and closely associated with cirrhosis, liver failure, and hepatocellular carcinoma (Parola and Pinzani, 2019). Acute and self-limiting fibrosis is generally regarded as a reversible, protective response to liver tissue injury. The persistent injurious stimuli in the liver gives rise to the accumulation of extracellular matrix (ECM) components, which largely disrupt the normal architecture and functioning of the liver, liver fibrosis irreversibly deteriorates to advanced cirrhosis with life-threatening consequences (Kisseleva and Brenner, 2021). Hepatic stellate cells (HSCs) are dominant contributors to fibrogenesis in the injured liver. Previous studies have shown that activated HSCs could transdifferentiate into myofibroblasts, which further produce amounts of main components of ECM, including collagen type.
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