Bletilla striata polysaccharides alleviate metabolic dysfunction-associated steatotic liver disease through enhancing hepatocyte RelA/ HNF1α signaling

Bletilla striata polysaccharides (BSP) have antioxidant, immune regulation, and anti-fibrotic activities. However, the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease (MASLD) have not been fully understood. To investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclear factor kappa B p65 (RelA)/hepatocyte nuclear factor-1 alpha (HNF1α) signaling. A mouse model of MASLD was induced by feeding with a high-fat-diet (HFD) and a hepatocyte model of steatosis was induced by treatment with sodium oleate (SO) and sodium palmitate (SP). The therapeutic effects of BSP on MASLD were examined in vivo and in vitro. The mechanisms underlying the action of BSP were analyzed for their effect on lipid metabolism disorder, endoplasmic reticulum (ER) stress, and the RelA/HNF1α signaling. HFD feeding reduced hepatocyte RelA and HNF1α expression, induced ER stress, lipid metabolism disorder, and necroptosis in mice, which were significantly mitigated by treatment with BSP. Furthermore, treatment with BSP or BSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate (SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation, and lipid peroxidation, and enhancing the expression of RelA, and HNF1α. The therapeutic effects of BSP on MASLD were partially abrogated by RELA silencing in mice and RELA knockout in hepatocytes. RELA silencing or knockout significantly down-regulated HNF1α expression, and remodeled ER stress and oxidative stress responses during hepatic steatosis. Treatment with BSP ameliorates MASLD, associated with enhancing the RelA/HNF1α signaling, remodeling ER stress and oxidative stress responses in hepatocytes.