Animal and Imaging core facility, Dasman Diabetes Institute, Dasman, Kuwait.
Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, Montréal, Quebec, Canada.
Obes Rev. 2021 Aug;22(8):e13248. doi: 10.1111/obr.13248. Epub 2021 Mar 18.
Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin resistance, pancreatic ß-cell dysfunction, type 2 diabetes, atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin, catalyzed by different sphingomyelinases, including neutral sphingomyelinase 2 (nSMase2), whose dysregulation appears to underlie many of the inflammation-related pathologies. In this review, we discuss the current knowledge on the biochemistry of nSMase2 and ceramide production and its regulation by inflammatory cytokines, with particular reference to cardiometabolic diseases. nSMase2 contribution to pathogenic processes appears to involve cyclical feed-forward interaction with proinflammatory cytokines, such as TNF-α and IL-1ß, which activate nSMase2 and the production of ceramides, that in turn triggers the synthesis and release of inflammatory cytokines. We elaborate these pathogenic interactions at the molecular level and discuss the potential therapeutic benefits of inhibiting nSMase2 against inflammation-driven cardiometabolic diseases.
鞘脂类，特别是神经酰胺，在与代谢综合征相关的病理生理过程中发挥着重要作用，其与胰岛素抵抗、胰岛β细胞功能障碍、2 型糖尿病、动脉粥样硬化、炎症、非酒精性脂肪性肝炎和癌症的发生发展有关。神经酰胺是通过鞘磷脂的水解产生的，由不同的鞘磷脂酶催化，包括中性鞘磷脂酶 2（nSMase2），其功能失调似乎是许多与炎症相关的病理学的基础。在这篇综述中，我们讨论了 nSMase2 的生物化学和神经酰胺产生及其受炎症细胞因子调节的最新知识，特别提到了与心脏代谢疾病相关的知识。nSMase2 对致病过程的贡献似乎涉及与促炎细胞因子（如 TNF-α 和 IL-1β）的周期性正反馈相互作用，这些细胞因子激活 nSMase2 并产生神经酰胺，而神经酰胺又触发炎症细胞因子的合成和释放。我们在分子水平上详细阐述了这些致病相互作用，并讨论了抑制 nSMase2 对抗炎症驱动的心脏代谢疾病的潜在治疗益处。
