PloS one · 2024
Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Osawa Yosuke, Kawai Hironari, Nakashima Keigo, Nakaseko Yuichi, Suto Daisuke, Yanagida Keisuke, Hashidate-Yoshida Tomomi, Mori Taizo, Yoshio Sachiyo, Ohtake Takaaki, Shindou Hideo, Kanto Tatsuya
Аннотация
AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.
METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.
RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.
CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.
RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.
CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
Предметные рубрики MeSH
AnimalsSphingosineLysophospholipidsLiver CirrhosisMiceHepatic Stellate CellsPhosphotransferases (Alcohol Group Acceptor)HumansSphingosine-1-Phosphate ReceptorsFatty LiverMaleMice, KnockoutMice, Inbred C57BLLiverCholine DeficiencyEndothelial CellsReceptors, LysosphingolipidPyrazolesPyridinesSphingosine Kinase