Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Hepatocyte-specific RIG-I loss attenuates metabolic dysfunction-associated steatotic liver disease in mice via changes in mitochondrial respiration and metabolite profiles

  • Jin Kyung Seok (College of Pharmacy, The Catholic University of Korea) ;
  • Gabsik Yang (Department of Pharmacology, College of Korean Medicine, Woosuk University) ;
  • Jung In Jee (College of Pharmacy, The Catholic University of Korea) ;
  • Han Chang Kang (College of Pharmacy, The Catholic University of Korea) ;
  • Yong‑Yeon Cho (College of Pharmacy, The Catholic University of Korea) ;
  • Hye Suk Lee (College of Pharmacy, The Catholic University of Korea) ;
  • Joo Young Lee (College of Pharmacy, The Catholic University of Korea)
  • Received : 2024.06.21
  • Accepted : 2024.09.10
  • Published : 2024.10.15
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Abstract

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-IΔhep) 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-IΔhep 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.

Keywords

Acknowledgement

We thank Younggyu Kwon and Yuri Kang for their technical assistance.

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