Hepatocyte-specific RIG-I loss attenuates metabolic dysfunction-associated steatotic liver disease in mice via changes in mitochondrial respiration and metabolite profiles

• Published in: Toxicological research (Seoul) 2024, 40(4), , pp.683-695
• Main Authors: Seok, Jin Kyung, Yang, Gabsik, Jee, Jung In, Kang, Han Chang, Cho, Yong-Yeon, Lee, Hye Suk, Lee, Joo Young
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Original Article; Pharmacology/Toxicology; 예방의학
• ISSN: 1976-8257; 2234-2753
• DOI: 10.1007/s43188-024-00264-x

Pattern recognition receptor (PRR)-mediated inflammation is an important determinant of the initiation and progression of metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated whether RIG-I is involved in hepatic metabolic reprogramming in a high-fat diet (HFD)-induced MASLD model in hepatocyte-specific RIG-I-KO (RIG-I ∆hep ) mice. Our study revealed that hepatic deficiency of RIG-I improved HFD-induced metabolic imbalances, including glucose impairment and insulin resistance. Hepatic steatosis and liver triglyceride levels were reduced in RIG-I-deficient hepatocytes in HFD-induced MASLD mice, and this was accompanied by the reduced expression of lipogenesis genes, such as PPARγ, Dga2, and Pck1. Hepatic RIG-I deficiency alters whole-body metabolic rates in the HFD-induced MASLD model; there is higher energy consumption in RIG-I ∆hep mice. Deletion of RIG-I activated glycolysis and tricarboxylic acid (TCA) cycle-related metabolites in hepatocytes from both HFD-induced MASLD mice and methionine-choline-deficient diet (MCD)-fed mice. RIG-I deficiency enhanced AMPK activation and mitochondrial function in hepatocytes from HFD-induced MASLD mice. These findings indicate that deletion of RIG-I can activate cellular metabolism in hepatocytes by switching on both glycolysis and mitochondrial respiration, resulting in metabolic changes induced by a HFD and stimulation of mitochondrial activity. In summary, RIG-I may be a key regulator of cellular metabolism that influences the development of metabolic diseases such as MASLD.