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

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-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.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-024-00264-x.

Keywords: Metabolic disorder; Metabolic dysfunction-associated steatotic liver disease; Metabolism; Mitochondria; Pattern-recognition receptors.