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  • Title: Protective role of cGAS in NASH is related to the maintenance of intestinal homeostasis.
    Author: de Carvalho Ribeiro M, Cho Y, Mehta J, Wang X, Babuta M, Copeland C, Hussein H, Catalano D, Wang Y, Szabo G.
    Journal: Liver Int; 2023 Sep; 43(9):1937-1949. PubMed ID: 37222257.
    Abstract:
    BACKGROUND & AIMS: Various intracellular pathways regulate inflammation in NASH. Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that activates STING and plays a role in inflammatory diseases. Here, we explored the role of cGAS in hepatic damage, steatosis, inflammation, and liver fibrosis in mouse models of NASH. METHODS: cGAS deficient (cGAS-KO) and STING deficient (STING-KO) mice received high fat-high cholesterol-high sugar diet (HF-HC-HSD) or relevant control diets. Livers were evaluated after 16 or 30 weeks. RESULTS: HF-HC-HSD diet, both at 16 and 30 weeks, resulted in increased cGAS protein expression as well as in increased ALT, IL-1β, TNF-α and MCP-1 in wild-type (WT) mice compared to controls. Surprisingly, liver injury, triglyceride accumulation, and inflammasome activation were greater in HF-HC-HSD cGAS-KO compared to WT mice at 16 and to a lesser extent at 30 weeks. STING, a downstream target of cGAS was significantly increased in WT mice after HF-HC-HSD. In STING-KO mice after HF-HC-HSD feeding, we found increased ALT and attenuated MCP1 and IL-1β expression compared to WT mice. Markers of liver fibrosis were increased in cGAS- and STING-KO mice compared to WT on HF-HC-HSD. We discovered that cGAS-KO mice had a significant increase in circulating endotoxin levels on HF-HC-HSD that correlated with changes in intestinal morphology which was exacerbated by HF-HC-HSD compared to WT mice. CONCLUSION: Our findings indicate that cGAS or STING deficiency exacerbate liver damage, steatosis, and inflammation in HF-HC-HSD diet-induced NASH, which might be linked to the disruption of the gut barrier.
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