SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors
SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors
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DOI：
10.1016/j.biopha.2023.115586
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发表时间：
2023-12-01
影响因子：
7.5
通讯作者：
Wang，Ru
中科院分区：
文献类型：
--
作者：
Sun，Qin;Xing，Xiaorui;Wang，Ru
以能量平衡失调为特征的代谢性疾病已成为全球健康的主要挑战。代谢性疾病患者很可能出现多种脂质代谢并发症，例如肥胖、胰岛素抵抗和脂肪肝。因此，靶向脂质代谢中的枢纽基因可以全身性地改善代谢性疾病，沿着并发症。硬脂酰辅酶A去饱和酶1（stearoyl-CoA desaturase 1，SCD 1）是将新生儿或饮食来源的饱和脂肪酸（saturated fatty acids，SFA）去饱和生成单不饱和脂肪酸（monounsaturated fatty acids，MUFAs）的关键酶。SCD 1通过响应和整合由合成的MUFA介导的多层内源性刺激来维持代谢和组织稳态。它关键地调节无数的生理过程，包括能量稳态、发育、自噬、肿瘤发生和炎症。SCD 1的异常转录和表观遗传激活调节AMPK/ACC、SIRT 1/PGC 1 α、NcDase/Wnt等，导致脂质异常蓄积，从而促进肥胖、非酒精性脂肪肝、糖尿病和癌症的进展。本文综述了SCD 1在代谢稳态、炎症和自噬中的病理生理功能的整合机制。从翻译的角度来看，已经开发了有效的SCD 1抑制剂来治疗各种类型的癌症。因此，我们讨论了多学科的进展，大大加快了SCD 1新抑制剂的发展。总之，除了癌症治疗外，SCD 1可能是同时对抗多种代谢并发症的有希望的靶点。
Metabolic diseases, featured with dysregulated energy homeostasis, have become major global health challenges. Patients with metabolic diseases have high probability to manifest multiple complications in lipid metabolism, e.g. obesity, insulin resistance and fatty liver. Therefore, targeting the hub genes in lipid metabolism may systemically ameliorate the metabolic diseases, along with the complications. Stearoyl-CoA desaturase 1(SCD1) is a key enzyme that desaturates the saturated fatty acids (SFAs) derived fromde novolipogenesis or diet to generate monounsaturated fatty acids (MUFAs). SCD1 maintains the metabolic and tissue homeostasis by responding to, and integrating the multiple layers of endogenous stimuli, which is mediated by the synthesized MUFAs. It critically regulates a myriad of physiological processes, including energy homeostasis, development, autophagy, tumorigenesis and inflammation. Aberrant transcriptional and epigenetic activation of SCD1 regulates AMPK/ACC, SIRT1/PGC1α, NcDase/Wnt, etc, and causes aberrant lipid accumulation, thereby promoting the progression of obesity, non-alcoholic fatty liver, diabetes and cancer. This review critically assesses the integrative mechanisms of the (patho)physiological functions of SCD1 in metabolic homeostasis, inflammation and autophagy. For translational perspective, potent SCD1 inhibitors have been developed to treat various types of cancer. We thus discuss the multidisciplinary advances that greatly accelerate the development of SCD1 new inhibitors. In conclusion, besides cancer treatment, SCD1 may serve as the promising target to combat multiple metabolic complications simultaneously.