Sirt6 enhances macrophage lipophagy and improves lipid metabolism disorder by regulating the Wnt1/β-catenin pathway in atherosclerosis

作者：Tingting Wang, Zheng Cheng, Ran Zhao, Jin Cheng, He Ren, Pengke Zhang, Pengyun Liu, Qimeng Hao, Qian Zhang, Xiaolei Yu, Dongdong Sun, Dongwei Zhang · 发表于：Lipids in Health and Disease · 年份：2023 · DOI：10.1186/s12944-023-01891-3 · 被引用次数：20 · 研究领域：Cardiovascular Disease and Adiposity、Adipokines, Inflammation, and Metabolic Diseases、Autophagy in Disease and Therapy

Abstract Lipid metabolism disorders are considerably involved in the pathology of atherosclerosis; nevertheless, the fundamental mechanism is still largely unclear. This research sought to examine the function of lipophagy in lipid metabolism disorder-induced atherosclerosis and its fundamental mechanisms. Previously, Sirt6 has been reported to stimulate plaque stability by promoting macrophage autophagy. However, its role in macrophage lipophagy and its relationship with Wnt1 remains to be established. In this study, ApoE −/− : Sirt6 −/− and ApoE −/− : Sirt6Tg mice were used and lipid droplets were analysed via transmission electron microscopy and Bodipy 493/503 staining in vitro. Atherosclerotic plaques in ApoE −/− : Sirt6 −/− mice showed greater necrotic cores and lower stability score. Reconstitution of Sirt6 in atherosclerotic mice improved lipid metabolism disorder and prevented the progression of atherosclerosis. Furthermore, macrophages with Ac-LDL intervention showed more lipid droplets and increased expression of adipophilin and PLIN2. Reconstitution of Sirt6 recruited using SNF2H suppressed Wnt1 expression and improved lipid metabolism disorder by promoting lipophagy. In addition, downregulation of Sirt6 expression in Ac-LDL-treated macrophages inhibited lipid droplet degradation and stimulated foam cell formation. Innovative discoveries in the research revealed that atherosclerosis is caused by lipid metabolism disorders due to downregulated Sirt6 expression. Thus...