Some paradoxes and unresolved aspects of hepatic de novo lipogenesis

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.