Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.

血管生成素样蛋白3（ANGPTL3）以其作为脂蛋白和内皮脂肪酶的抑制剂而闻名。由于遗传学或药理学的ANGPTL3抑制作用能够显着减少循环脂蛋白，并且在这种抑制作用下有记载的心脏保护作用，因此ANGPTL3已成为新兴的治疗目标，正在对其抗体和反义寡核苷酸（ASO）治疗剂进行临床测试。虽然抗体对循环ANGPTL3具有相对选择性，但ASO也会消耗肝细胞内蛋白质，并且有新证据显示ANGPTL3在肝脏中具有细胞自主功能。这些措施包括调节肝细胞葡萄糖和脂肪酸摄取，胰岛素敏感性，LDL / VLDL残余摄取，VLDL组装/分泌，多不饱和脂肪酸（PUFA）和PUFA衍生的脂质介体含量以及基因表达。在本综述中，我们详细阐述（i）为何ANGPTL3被认为是最有希望的新心脏代谢治疗靶标之一，以及（ii）其肝内或细胞自主功能的当前证据。