SIRT3 ameliorates hepatic inflammation, oxidative stress, and fibrosis in HFD- or MCD diet-fed mice

Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), has emerged as one of the leading causes of cirrhosis and hepatocellular carcinoma. Currently, no specific pharmacological treatment is available for MASLD/MASH patients. Sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial metabolism, antioxidant defenses, and the maintenance of cellular homeostasis. To investigate the effects of SIRT3 overexpression on inflammation, oxidative stress, and fibrosis in mice. Mice were injected an SIRT3 overexpressed adeno-associated virus (AAV-SIRT3) vector or a control vector (AAV-GFP) by intravenous tail vein injection. Six-week-old mice were randomly assigned to four groups: CD-GFP, CD-SIRT3, HFD-GFP, and HFD-SIRT3. Mice received tail vein injections according to the group assignment, followed by a 12-week feeding regimen with either a chow diet (CD) or a high-fat diet (HFD). Eleven-week-old mice were randomly divided into four groups: MCS-GFP, MCS-SIRT3, MCD-GFP, and MCD-SIRT3 groups. Tail vein injections were administered prior to a 5-week dietary intervention using either a methionine-choline-sufficient diet (MCS) or a methionine-choline-deficient diet (MCD). In both HFD-and MCD diet-fed mice, SIRT3 overexpression improved serum ALT and AST levels, decreased hepatic TG levels, reduced macrophage infiltration, and decreased inflammatory signals and cytokines. In addition, hepatic SIRT3 overexpression reduced ROS production and increased antioxidative protein levels, such as HO-1, NQO1, and NRF2, as well as increased Mitochondrial SOD2 deacetylation. Furthermore, SIRT3 overexpression decreased the levels of fibrogenic genes including Col1α1, Col3α1, and α-SMA. SIRT3 overexpression significantly reduced hepatic lipid accumulation, inflammation, oxidative stress, and fibrosis in HFD-and MCD diet-fed mice.