Homocysteine Alleviates Nonalcoholic Steatohepatitis by Accelerating ACTG1-mediated TAK1 Lysosomal Degradation in Hepatocytes

Recent studies showed the role of homocysteine (Hcy) in non-alcoholic steatohepatitis (NASH) remains unclear. The aim of this study is to reveal the function and potential mechanism of Hcy in NASH. In vitro, qRT-PCR showed that Hcy reduced the expression of lipid metabolism related- and inflammation related-genes in palmitic acid and oleic acid (PAOA)-induced hepatocytes. Oil Red O (ORO)-staining exhibited that the PAOA-induced hepatocyte steatosis was alleviated by Hcy treatment. In vivo, Hcy supplementation ameliorated choline-deficient high-fat diet (CDHFD)-induced NASH process. RNA-seq analysis and Western blot suggested Hcy suppress the activation of MAPK signaling in NASH process by inhibiting TAK1 expression in vivo and in vitro. MG132 and chloroquine (CQ) incubation assay showed the loss of TAK1 in Hcy therapy was restored by CQ treatment, indicating the Hcy accelerated TAK1 lysosomal degradation. We further revealed the Hcy accelerated the ACTG1-mediated lysosomal degradation of TAK1 and ACTG1 was required for Hcy to ameliorate PAOA-induced hepatocyte steatohepatitis. Our findings demonstrated the Hcy attenuates NASH process via accelerating ACTG1-mediated TAK1 lysosomal degradation in vitro and in vivo, which is a previously unappreciated signaling mechanism and therapeutic effect in NASH.