PDF(Pubmed)
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.
摘要：
乙酰辅酶A合成酶短链家族成员1（ACSS1）使用乙酸产生线粒体乙酰辅酶A，并通过去乙酰化酶3进行调节。我们产生了一个ACSS1-乙酰化（Ac）模拟小鼠，其中赖氨酸635突变为谷氨酰胺(K635Q)。雄性Acss1K635Q/K635Q小鼠较小，代谢率较高，血液中的乙酸盐含量较高，肝脏/血清ATP和乳酸含量下降。禁食48小时后,Acss1K635Q/K635Q小鼠呈现低温和肝脏畸变,包括扩大，变色,脂滴积累，和微脂肪变性，符合非酒精性脂肪性肝病（NAFLD）。RNA测序分析表明脂肪酸代谢失调，细胞衰老,和肝脏脂肪变性网络，与NAFLD一致。禁食的Acss1K635Q/K635Q小鼠肝脏显示脂肪酸合成酶（FASN）和硬脂酰辅酶A去饱和酶1（SCD1）增加，两者都与NAFLD有关，并增加了碳水化合物反应元件结合蛋白与Fasn和Scd1增强子区域的结合。最后,肝脏脂质组学显示神经酰胺升高，溶血磷脂酰乙醇胺，和溶血磷脂酰胆碱，都与NAFLD有关。因此，我们认为ACSS1-K635-Ac失调会导致异常的脂质代谢，细胞衰老,和NAFLD。
