Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Schisandra chinensis lignans and polysaccharides alleviate MASH via ASAH1-mediated regulation of hepatic ceramide homeostasis.
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Chen Qi, Wang Leyi, Zhou Zhihao, Ding Ke, Wang Zhongbo, Jia Nan, Yan Yiyue, Xie Lin, Wang Guangji, Hu Kangrui, Liang Yan
Аннотация
BACKGROUND: The pathogenesis and progression of metabolic steatohepatitis (MASH) is a complex process characterized by excessive lipid accumulation, inflammation, and fibrosis. It is urgent to explore a novel approach which is safe and effective.
PURPOSE: Our current research aimed to explore the pathogenesis of MASH, evaluate the therapeutic potential of Schisandra chinensis lignan extracts (SLE) and polysaccharides (SCP), and elucidate their molecular mechanisms for treating MASH.
METHODS: This study constructed a methionine choline deficiency (MCD) diet induced MASH mouse model (in vivo) and a palmitic acid (PA) treated AML-12 liver cell model (in vitro). Combining lipidomics, knockout, RT-PCR, western-blotting, etc., the hepatoprotective effects and molecular mechanisms of SLE and SCP were studied.
RESULTS: Both SLE and SCP could effectively reverse steatosis, reduce serum transaminase levels, inhibit pro-inflammatory cytokines (TNF‑α, IL‑6, IL‑1β, etc.) and fibrosis genes (COL1A1, α‑SMA), and alleviate oxidative stress, exerting therapeutic effects on hepatic damage in MASH mice. Time‑course lipidomics demonstrated that ceramides (Cers) obviously accumulated during the progression of MASH, accompanied by a gradual downregulation of N-acyl sphingosine amide hydrolase 1 (ASAH1). SLE and SCP could also significantly alleviate lipid deposition, oxidative stress enhancement, and upregulation of inflammatory/fibrotic factors in AML-12 liver cells induced by PA treatment. Inhibition or knockout of ASAH1 exacerbated Cer accumulation, oxidative stress, and inflammatory/fibrotic response levels in hepatocytes and in MASH mouse livers, fully confirming the crucial role of ASAH1 in MASH pathogenesis. More importantly, the administration of SLE and SCP could significantly reverse the downregulation of ASAH1, thereby promoting Cer hydrolysis metabolism, alleviating Cer accumulation, and reducing liver damage caused by MASH modeling.
CONCLUSION: Therefore, this study innovatively revealed the pathological mechanism of MASH from the perspective of Cer metabolism, and for the first time confirmed that both SLE and SCP could exert therapeutic effects on MASH by upregulating ASAH1 expression, promoting Cer hydrolysis, reducing hepatocytic Cer accumulation, thereby alleviating liver damage caused by excessive Cers.
PURPOSE: Our current research aimed to explore the pathogenesis of MASH, evaluate the therapeutic potential of Schisandra chinensis lignan extracts (SLE) and polysaccharides (SCP), and elucidate their molecular mechanisms for treating MASH.
METHODS: This study constructed a methionine choline deficiency (MCD) diet induced MASH mouse model (in vivo) and a palmitic acid (PA) treated AML-12 liver cell model (in vitro). Combining lipidomics, knockout, RT-PCR, western-blotting, etc., the hepatoprotective effects and molecular mechanisms of SLE and SCP were studied.
RESULTS: Both SLE and SCP could effectively reverse steatosis, reduce serum transaminase levels, inhibit pro-inflammatory cytokines (TNF‑α, IL‑6, IL‑1β, etc.) and fibrosis genes (COL1A1, α‑SMA), and alleviate oxidative stress, exerting therapeutic effects on hepatic damage in MASH mice. Time‑course lipidomics demonstrated that ceramides (Cers) obviously accumulated during the progression of MASH, accompanied by a gradual downregulation of N-acyl sphingosine amide hydrolase 1 (ASAH1). SLE and SCP could also significantly alleviate lipid deposition, oxidative stress enhancement, and upregulation of inflammatory/fibrotic factors in AML-12 liver cells induced by PA treatment. Inhibition or knockout of ASAH1 exacerbated Cer accumulation, oxidative stress, and inflammatory/fibrotic response levels in hepatocytes and in MASH mouse livers, fully confirming the crucial role of ASAH1 in MASH pathogenesis. More importantly, the administration of SLE and SCP could significantly reverse the downregulation of ASAH1, thereby promoting Cer hydrolysis metabolism, alleviating Cer accumulation, and reducing liver damage caused by MASH modeling.
CONCLUSION: Therefore, this study innovatively revealed the pathological mechanism of MASH from the perspective of Cer metabolism, and for the first time confirmed that both SLE and SCP could exert therapeutic effects on MASH by upregulating ASAH1 expression, promoting Cer hydrolysis, reducing hepatocytic Cer accumulation, thereby alleviating liver damage caused by excessive Cers.