Jones John G
Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
NPJ Metab Health Dis. 2024 Aug 2;2(1):18. doi: 10.1038/s44324-024-00020-7.
Hepatic de novo lipogenesis (DNL) is a critical pathway in both liver intermediary metabolism and whole-body nutrient management. In the setting of excessive caloric intake, increased DNL fluxes are implicated in the pathogenesis of metabolic-associated steatotic liver disease (MASLD). As a result, there is intense interest both in the measurement of DNL activity and in gaining a better understanding on how this drives MASLD development. While much progress has been made towards these objectives, a number of intriguing uncertainties and paradoxes remain. This short perspective will focus on some of these aspects, namely a), how DNL contributes to triglyceride overload, b), the timing of DNL pathway activation with nutrient availability, c) the sources of acetyl-CoA for DNL and d), the sources of NADPH reducing equivalents for DNL. The implications of these uncertainties on pharmacological targeting of hepatic DNL activity will also be discussed.
肝脏从头脂肪生成（DNL）是肝脏中间代谢和全身营养管理中的关键途径。在热量摄入过多的情况下，DNL通量增加与代谢相关脂肪性肝病（MASLD）的发病机制有关。因此，人们对DNL活性的测量以及更好地理解其如何驱动MASLD的发展都有着浓厚的兴趣。虽然在实现这些目标方面已经取得了很大进展，但仍存在一些有趣的不确定性和矛盾之处。本简短综述将聚焦于其中一些方面，即a）DNL如何导致甘油三酯过载，b）DNL途径随营养物质可利用性的激活时间，c）DNL的乙酰辅酶A来源，以及d）DNL的NADPH还原当量来源。还将讨论这些不确定性对肝脏DNL活性药物靶向治疗的影响。
