Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
College of Computer, Math, and Natural Sciences, College of Behavioral and Social Sciences, University of Maryland, College Park, MD, USA.
Adv Exp Med Biol. 2020;1276:197-222. doi: 10.1007/978-981-15-6082-8_13.
Comparative gene identification-58 (CGI-58), also known as α/β-hydrolase domain-containing 5 (ABHD5), is a member of a large family of proteins containing an α/β-hydrolase-fold. CGI-58 is well-known as the co-activator of adipose triglyceride lipase (ATGL), which is a key enzyme initiating cytosolic lipid droplet lipolysis. Mutations in either the human CGI-58 or ATGL gene cause an autosomal recessive neutral lipid storage disease, characterized by the excessive accumulation of triglyceride (TAG)-rich lipid droplets in the cytoplasm of almost all cell types. CGI-58, however, has ATGL-independent functions. Distinct phenotypes associated with CGI-58 deficiency commonly include ichthyosis (scaly dry skin), nonalcoholic steatohepatitis, and hepatic fibrosis. Through regulated interactions with multiple protein families, CGI-58 controls many metabolic and signaling pathways, such as lipid and glucose metabolism, energy balance, insulin signaling, inflammatory responses, and thermogenesis. Recent studies have shown that CGI-58 regulates the pathogenesis of common metabolic diseases in a tissue-specific manner. Future studies are needed to molecularly define ATGL-independent functions of CGI-58, including the newly identified serine protease activity of CGI-58. Elucidation of these versatile functions of CGI-58 may uncover fundamental cellular processes governing lipid and energy homeostasis, which may help develop novel approaches that counter against obesity and its associated metabolic sequelae.
比较基因鉴定-58（CGI-58），也称为α/β-水解酶结构域包含 5（ABHD5），是包含α/β-水解酶折叠的一大类蛋白质家族的成员。CGI-58 是脂肪甘油三酯脂肪酶（ATGL）的共激活因子而广为人知，ATGL 是启动细胞质脂滴脂肪分解的关键酶。人类 CGI-58 或 ATGL 基因的突变导致常染色体隐性中性脂质贮积病，其特征是几乎所有细胞类型的细胞质中甘油三酯（TAG）丰富的脂滴过度积累。然而，CGI-58 具有 ATGL 非依赖性功能。与 CGI-58 缺乏相关的独特表型通常包括鱼鳞癣（鳞屑干燥皮肤）、非酒精性脂肪性肝炎和肝纤维化。通过与多个蛋白家族的调节相互作用，CGI-58 控制许多代谢和信号通路，如脂质和葡萄糖代谢、能量平衡、胰岛素信号、炎症反应和产热。最近的研究表明，CGI-58 以组织特异性方式调节常见代谢疾病的发病机制。需要进一步的研究来从分子水平上定义 CGI-58 的 ATGL 非依赖性功能，包括 CGI-58 新发现的丝氨酸蛋白酶活性。阐明 CGI-58 的这些多功能功能可能揭示控制脂质和能量稳态的基本细胞过程，这可能有助于开发针对肥胖及其相关代谢后果的新方法。
