State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, College of Life Science, Henan Normal university, Xinxiang 453007, China.
Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Biochim Biophys Acta Mol Basis Dis. 2024 Feb;1870(2):166960. doi: 10.1016/j.bbadis.2023.166960. Epub 2023 Nov 17.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.
特发性肺纤维化（IPF）是一种病因不明的进行性致命性间质性肺疾病。新出现的证据表明，肺泡上皮反复损伤引起的代谢稳态失衡是 IPF 的潜在发病机制。蛋白质组学分析表明，乙酰辅酶 A 合成酶短链家族成员 3（ACSS3）在特发性肺纤维化患者和博来霉素诱导纤维化的小鼠中的表达降低。ACSS3 参与脂质和碳水化合物代谢。ACSS3 的表达增加会下调肉毒碱棕榈酰基转移酶 1A（CPT-1A），导致脂滴积累，而增强的糖酵解则导致 A549 细胞细胞外乳酸水平升高。ACSS3 通过丙酸代谢增加琥珀酰辅酶 A 的产生，并减少肺泡上皮细胞中乙酰辅酶 A 和 ATP 的产生。Acss3 的过表达通过 CPT1A 缺乏抑制 ECM 的过度沉积，并减轻体内 micro-CT 确定的磨玻璃样混浊。简而言之，我们的研究结果表明，ACSS3 通过 CPT1A 缺乏降低脂肪酸氧化，并增强无氧糖酵解，这种代谢重编程通过减少线粒体分裂和融合、增加 ROS 产生、抑制自噬、促进细胞凋亡来使肺泡上皮细胞失活，表明 ACSS3 可能是肺纤维化的潜在治疗靶点。
