Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered metabolism, cell senescence, and nonalcoholic fatty liver disease

Guogang Xu, Songhua Quan, Joseph Schell, Yucheng Gao, Mahboubeh Varmazyad, Prethish Sreenivas, Diego Cruz, Haiyan Jiang, Meixia Pan, Xianlin Han, Juan Pablo Palavicini, Peng Zhao, Xiaoli Sun, Erik D. Marchant, Blake Rasmussen, Guannan Li, Sakie Katsumura, Masahiro Morita, Erin Munkácsy, Nobuo HorikoshiE. Sandra Chocron, David Gius

Research output: Contribution to journalArticlepeer-review

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 Acss1K635Q/K635Q mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, Acss1K635Q/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 Acss1K635Q/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.

Original languageEnglish (US)
Article numbereadj5942
JournalScience Advances
Volume10
Issue number20
DOIs
StatePublished - May 2024

ASJC Scopus subject areas

  • General

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