Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Pharmacol Ther. 2023 May;245:108401. doi: 10.1016/j.pharmthera.2023.108401. Epub 2023 Mar 30.
Obesity is a key risk factor for the development of metabolic disease. Bioactive sphingolipid metabolites are among the lipids increased in obesity. Obesogenic saturated fatty acids are substrates for serine palmitoyltransferase (SPT) the rate-limiting step in de novo sphingolipid biosynthesis. The mammalian orosomucoid-like protein isoforms ORMDL1-3 negatively regulate SPT activity. Here we summarize evidence that dysregulation of sphingolipid metabolism and SPT activity correlates with pathogenesis of obesity. This review also discusses the current understanding of the function of SPT and ORMDL in obesity and metabolic disease. Gaps and limitations in current knowledge are highlighted together with the need to further understand how ORMDL3, which has been identified as an obesity-related gene, contributes to the pathogenesis of obesity and development of metabolic disease related to its physiological functions. Finally, we point out the needs to move this young field of research forward.
肥胖是代谢性疾病发展的一个关键风险因素。生物活性神经鞘脂代谢物是肥胖症中增加的脂质之一。致肥胖饱和脂肪酸是丝氨酸棕榈酰转移酶（SPT）的底物，SPT 是从头合成神经鞘脂生物合成的限速步骤。哺乳动物粘蛋白样蛋白同工型 ORMDL1-3 负调节 SPT 活性。在这里，我们总结了神经鞘脂代谢和 SPT 活性失调与肥胖发病机制相关的证据。这篇综述还讨论了目前对 SPT 和 ORMDL 在肥胖和代谢性疾病中的功能的理解。突出了当前知识中的差距和局限性，以及需要进一步了解作为肥胖相关基因的 ORMDL3 如何通过其生理功能促进肥胖发病机制和代谢性疾病的发展。最后，我们指出需要推动这一新兴研究领域向前发展。
