Recombinant hirudin prevents against nonalcoholic fatty liver disease by modulating PAR1/JAK2/STAT5/STAT3/CD36 pathway

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease. Recombinant hirudin (R-Hirudin) is an manufactured product produced by genetic engineering technology which possesses antithrombotic and hypolipidemic effects, however, the role and molecular mechanisms of R-Hirudin in NAFLD are not clear. Therefore, the aim of this study was to explore the potential mechanism of action and role of R-Hirudin in NAFLD. METHOD: AML12 cells were induced with palmitic acid (PA) to construct an in vitro NAFLD model. C57BL/6 J male mice were continuously fed a high-fat diet (HFD) for 12 weeks to establish an in vivo NAFLD model. R-Hirudin was administered subcutaneously twice daily for 12 weeks to study the effect of R-Hirudin on NAFLD, and Vitamin E was used as a positive control. H&E staining as well as ALT, AST kit were used to assess the liver injury. MASSON staining was used to assess the extent of liver fibrosis. Nile red staining, Oil red O staining and TG, TC, LDL-C, HDL-C kit were used to assess the degree of lipid droplet infiltration and lipid accumulation. LDH, MDA, SOD, GSH kit was used to assess the level of oxidative stress in vivo and in vitro. Immunofluorescence staining and western blot assay were used to assess the changes in lipid metabolism and inflammatory factor-related indices as well as target proteins in liver and cells. Chromatin immunoprecipitation analysis, dual luciferase gene reporter test and DNA pulldown assay were used to verify the relationship between STAT3, STAT5 and CD36. RESULT: R-Hirudin significantly improved hepatic lipid accumulation, hepatic steatosis, oxidative stress and liver inflammation in the NAFLD mice. At the same time, R-Hirudin attenuated PA-induced AML12 lipid accumulation and inflammatory response. In in vitro and in vivo experiments, R-Hirudin significantly down-regulated PAR1, CD36 and p-STAT3 protein levels and up-regulated p-JAK2 and p-STAT5 protein levels. Knockdown of CD36 ameliorated lipid accumulation and inflammatory responses. In addition, PAR1 regulates the STAT5/STAT3/CD36 signaling pathway by modulating JAK2. Finally, CHIP, dual luciferase gene reporter assay, and DNA pulldown assay verified that the transcription factors STAT5 and STAT3 bind to fragments on the CD36 promoter to affect the activity of CD36. CONCLUSION: The results indicated that R-Hirudin might ameliorate steatosis, lipid accumulation and inflammatory response through PAR1/JAK2/STAT5/STAT3/CD36 signaling pathway and thus alleviate NAFLD.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Demonstrates recombinant leech hirudin prevents NAFLD in murine models via PAR1/JAK2/STAT5/STAT3/CD36 signaling — extends hirudin pharmacology into metabolic liver disease.

Leech-derived molecules this paper discusses, each with a full profile in the ASH compound registry:

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