Substrate supply, compartmentation, and utilization in hepatic de novo lipogenesis

Hepatic de novo lipogenesis (DNL) is a fundamental process that supports energy storage, membrane biogenesis, and lipid signaling. However, chronically elevated hepatic DNL is a risk factor for insulin resistance and liver fat accumulation. If sustained, this can drive inflammation and fibrosis, with progression to cirrhosis and sometimes hepatocellular carcinoma, as well as numerous cardiometabolic comorbidities. Therefore, new discoveries on the basic mechanisms that control hepatic DNL may enable therapeutic modulation that improves major health outcomes. This review synthesizes recent advances in how the liver channels lipogenic substrates through mitochondrial and cytosolic pathways into DNL. It also highlights how these substrates regulate lipogenic flux by supplying cytosolic acetyl-CoA and NADPH.