Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs. During clinical evaluation of a systemically distributed ACC inhibitor, unexpected dose-dependent reductions in platelet count were observed. While platelet count reductions were not observed in rat and dog toxicology studies, subsequent studies in cynomolgus monkeys recapitulated these platelet count reductions with a similar concentration response to that in humans. These studies, along with ex vivo human megakaryocyte maturation studies, demonstrate that platelet lowering is a consequence of DNL inhibition likely to result in impaired megakaryocyte demarcation membrane formation. These observations demonstrate that while DNL is a minor quantitative contributor to global lipid balance in humans, DNL is essential to specific lipid pools of physiological importance.

乙酰辅酶A羧化酶（ACC）催化新生脂肪形成（DNL）的第一步。ACC的药物抑制作用已引起广泛疾病的治疗干预。在这里，我们证明了ACC和DNL对于人类和猴子的血小板生成至关重要，但对啮齿动物或狗而言则非如此。在对全身分布的ACC抑制剂进行临床评估期间，观察到了血小板计数的意外剂量依赖性降低。虽然在大鼠和狗毒理学研究中未观察到血小板计数减少，但随后在食蟹猴中进行的研究概括了这些血小板计数减少，其浓度响应与人相似。这些研究以及离体人类巨核细胞成熟研究，证明血小板降低是DNL抑制的结果，可能导致巨核细胞分界膜形成受损。这些观察结果表明，尽管DNL在人类总体脂质平衡中仅占很小的数量，但DNL对于具有重要生理意义的特定脂质库至关重要。