Angiopoietin-like protein (ANGPTL) family members, mainly ANGPTL3, ANGPTL4 and ANGPTL8, are physiological inhibitors of lipoprotein lipase (LPL), and play a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 has been described by different names in various studies and has been ascribed various functions at the systemic and cellular levels. Circulating ANGPTL8 originates mainly from the liver and to a smaller extent from adipose tissues. In the blood, ANGPTL8 forms a complex with ANGPTL3 or ANGPTL4 to inhibit LPL in fed or fasted conditions, respectively. Evidence is emerging for additional intracellular and receptor-mediated functions of ANGPTL8, with implications in NFκB mediated inflammation, autophagy, adipogenesis, intra-cellular lipolysis and regulation of circadian clock. Elevated levels of plasma ANGPTL8 are associated with metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension and NAFLD/NASH, even though the precise relationship is not known. Whether ANGPTL8 has direct pathogenic role in these diseases, remains to be explored. In this review, we develop a balanced view on the proposed association of this protein in the regulation of several pathophysiological processes. We also discuss the well-established functions of ANGPTL8 in lipoprotein metabolism in conjunction with the emerging novel extracellular and intracellular roles of ANGPTL8 and the implicated metabolic and signalling pathways. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states should unveil new opportunities of therapeutic intervention for cardiometabolic disorders.

血管生成素样蛋白 (ANGPTL) 家族成员，主要是 ANGPTL3、ANGPTL4 和 ANGPTL8，是脂蛋白脂肪酶 (LPL) 的生理抑制剂，并且在响应营养线索的脂蛋白和甘油三酯代谢中起关键作用。ANGPTL8 在各种研究中被描述为不同的名称，并在系统和细胞水平上具有各种功能。循环中的 ANGPTL8 主要来自肝脏，少量来自脂肪组织。在血液中，ANGPTL8 与 ANGPTL3 或 ANGPTL4 形成复合物，分别在进食或禁食条件下抑制 LPL。ANGPTL8 的其他细胞内和受体介导功能的证据正在出现，这对 NFκB 介导的炎症、自噬、脂肪生成、细胞内脂肪分解和生物钟调节有影响。血浆 ANGPTL8 水平升高与代谢综合征、2 型糖尿病、动脉粥样硬化、高血压和 NAFLD/NASH 相关，尽管确切的关系尚不清楚。ANGPTL8 是否在这些疾病中具有直接致病作用，仍有待探索。在这篇综述中，我们对这种蛋白质在几种病理生理过程的调节中的拟议关联形成了一个平衡的观点。我们还讨论了 ANGPTL8 在脂蛋白代谢中的公认功能，以及 ANGPTL8 新出现的细胞外和细胞内作用以及相关的代谢和信号通路。了解 ANGPTL8 在各种组织和代谢状态中的不同功能应该为心脏代谢疾病的治疗干预提供新的机会。