Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
Department of Laboratory Medicine, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350001, China.
Int J Mol Sci. 2022 Sep 2;23(17):10042. doi: 10.3390/ijms231710042.
Obesity has become an extensive threat to human health due to associated chronic inflammation and metabolic diseases. Apoptosis-associated speck-like protein (ASC) is a critical link between inflammasome and apoptosis-inducing proteins. In this study, we aimed to clarify the role of ASC in lipid metabolism. With high-fat diet (HFD) and knockout leptin gene mice (/), we found that ASC expression in subcutaneous adipose tissue (SAT) correlated with obesity. It could also positively regulate the reprogramming of cellular energy metabolism. Stromal vascular fractions (SVF) cells derived from the SAT of mice or SVF from wild-type (WT) mice transfected with ASC siRNA were used to further investigate the underlying molecular mechanisms. We found ASC deficiency could lead to lipogenesis and inhibit lipolysis in SAT, aggravating lipid accumulation and impairing metabolic balance. In addition, our results showed that p53 and AMPKα expression were inhibited in SAT when ASC level was low. p53 and AMP-activated protein kinase α (AMPKα) were then assessed to elucidate whether they were downstream of ASC in regulating lipid metabolism. Our results revealed that ASC deficiency could promote lipid accumulation by increasing lipogenesis and decreasing lipolysis through p53/AMPKα axis. Regulation of ASC on lipid metabolism might be a novel therapeutic target for obesity.
肥胖症已成为威胁人类健康的一个重要因素，它与慢性炎症和代谢性疾病密切相关。凋亡相关斑点样蛋白（ASC）是衔接炎症小体和诱导细胞凋亡蛋白的关键蛋白。本研究旨在探讨 ASC 在脂代谢中的作用。通过高脂肪饮食（HFD）喂养和敲除瘦素基因（/）的小鼠模型，我们发现 ASC 在皮下脂肪组织（SAT）中的表达与肥胖程度相关，并且能够正向调控细胞能量代谢的重编程。进一步使用从 ASC 敲除小鼠 SAT 中分离得到的基质血管 Fraction（SVF）细胞或转染 ASC siRNA 的野生型（WT）小鼠的 SVF 细胞，深入研究其潜在的分子机制。结果发现 ASC 缺乏会导致 SAT 中的脂肪生成增加和脂肪分解抑制，加剧脂质堆积并损害代谢平衡。此外，我们的研究结果表明，当 ASC 水平降低时，SAT 中的 p53 和 AMPKα 的表达受到抑制。因此，我们评估了 p53 和 AMP 激活的蛋白激酶α（AMPKα）是否是 ASC 调节脂代谢的下游靶点。研究结果表明，ASC 缺乏可通过增加脂肪生成和减少脂肪分解，从而促进脂质堆积，其作用机制可能与 p53/AMPKα 轴有关。综上所述，ASC 对脂代谢的调节可能成为肥胖症治疗的新靶点。
