De novo lipogenesis

De novo lipogenesis (DNL) is the pathway by which the liver converts excess carbohydrates — primarily glucose and fructose — into fatty acids, packaged as triglycerides into VLDL or stored as hepatic fat. Two transcription factors drive the process: SREBP-1c, activated by insulin, and ChREBP, activated by intracellular sugar phosphates; both upregulate acetyl-CoA carboxylase and fatty acid synthase. Fructose is a more potent DNL substrate than glucose because it enters glycolysis downstream of the rate-limiting phosphofructokinase step, flooding hepatic acetyl-CoA largely unregulated; chronic surplus drives steatosis and is mechanistically linked to MASLD. Stable-isotope tracer studies (¹³C-acetate or deuterium water) estimate DNL accounts for roughly 15–25 % of hepatic triglycerides in MASLD patients — modest absolutely, yet malonyl-CoA from DNL simultaneously suppresses mitochondrial fatty-acid oxidation via carnitine palmitoyltransferase I, amplifying lipid accumulation. A non-randomized isocaloric controlled feeding study (Schwarz et al., 2017, n = 41 obese children) in which each participant served as their own control showed that replacing dietary sugar with starch for nine days reduced liver fat, DNL flux, and fasting insulin without altering calories — establishing a causal rather than associational role for sugar-derived DNL in pediatric hepatic steatosis. The evidence base remains weighted toward short-term human feeding studies and rodent models; long-term randomized data in adults with established MASLD are lacking.