Xu 2024 Sci Adv

Xu G, Quan S, Schell J, Gao Y, Varmazyad M, Sreenivas P, Cruz D, Jiang H, Pan M, Han X, Palavicini JP, Zhao P, Sun X, Marchant ED, Rasmussen BB, Li G, Katsumura S, Morita M, Munkácsy E, Horikoshi N, Chocron ES, Gius D (2024) Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered metabolism, cell senescence, and nonalcoholic fatty liver disease. Sci Adv 10:eadj5942. https://doi.org/10.1126/sciadv.adj5942

» PMID: 38758779 Open Access

Xu Guogang, Quan Songhua, Schell Joseph, Gao Yucheng, Varmazyad Mahboubeh, Sreenivas Prethish, Cruz Diego, Jiang Haiyan, Pan Meixia, Han Xianlin, Palavicini Juan Pablo, Zhao Peng, Sun Xiaoli, Marchant Erik D, Rasmussen Blake B, Li Guannan, Katsumura Sakie, Morita Masahiro, Munkacsy Erin, Horikoshi Nobuo, Chocron E Sandra, Gius David (2024) Sci Adv

Abstract: Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male Acss1^K635Q/K635Q mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, Acss1^K635Q/K635Q mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted Acss1^K635Q/K635Q mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to Fasn and Scd1 enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.

• Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Liver 

Coupling state: ET, LEAK, OXPHOS  Pathway: F, N, ROX  HRR: Oxygraph-2k 

2024-05