Sodium butyrate ameliorates liver fibrosis in metabolic dysfunction-associated steatohepatitis rats via miR-155-5p/SOCS1/PDGF signaling pathway

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease worldwide. Recently, short-chain fatty acids (SCFAs), as metabolites of intestinal flora, have been found to participate in the progression of MASLD. Sodium butyrate (NaB), one of the most important SCFAs, shows therapeutic potentials in MASLD and its mechanisms have not been fully understood. The present study aimed to investigate the effects of NaB on metabolic dysfunction-associated steatohepatitis (MASH) associated fibrosis as well as the underlying mechanisms.

Methods: Male Sprague-Dawley rats were randomly assigned to three groups: (i) control group, standard chow for 24 weeks; (ii) HFD group, high-fat and high-cholesterol diet (HFD) for 24 weeks; and (iii) HFD + NaB group, HFD for 24 weeks and NaB gavage for the last 16 weeks. Body weight, liver index (liver weight/body weight × 100%), serum parameters, and liver histology were analyzed to evaluate MASH and fibrosis severity. AML12, RAW264.7 and LX2 cell lines were used for in vitro study.

Results: Compared to MASH rats with fibrosis induced by 24-week HFD, NaB intervention alleviated the degree of hepatic steatosis, inflammation, hepatocyte ballooning, and fibrosis. Further mechanistic study showed that NaB supplementation significantly decreased miR-155-5p level in the liver and the serum of MASH rats, and the inhibition effects of miR-155-5p on suppressor of cytokine signaling 1 (SOCS1) in both hepatocytes and hepatic stellate cells (HSCs) were blunted when they were treated with NaB. Furthermore, NaB also significantly decreased the production of platelet-derived growth factor-BB (PDGF-BB), a pro-fibrotic mediator, in hepatocytes. NaB treatment on AML12 cells markedly impaired the proliferation ability of co-cultured LX2 cells. Moreover, NaB intervention or miR-155-5p mimics also interferes extracellular regulated protein kinases signaling in LX2 cells.

Conclusions: NaB intervention inhibited HSCs activation via miR-155-5p/SOCS1/PDGF signaling pathway and consequently relieved fibrosis in MASH rats. NaB might be a potential agent for the treatment of fibrosis in patients with MASH.

Keywords: Fibrosis; Metabolic dysfunction-associated steatohepatitis; Platelet-derived growth factor; Sodium butyrate; miR-155-5p.