De novo lipogenesis

De novo lipogenesis (DNL) is how your liver turns excess carbs, mainly glucose and fructose, into new fat. The fat is packaged as triglycerides into VLDL particles, or stored as liver fat. Two switches drive it: SREBP-1c (turned on by insulin) and ChREBP (turned on by sugar). Both ramp up the fat-building enzymes (acetyl-CoA carboxylase and fatty acid synthase). Fructose is an even stronger DNL fuel than glucose. That is because it skips the main control point of sugar-burning (phosphofructokinase), flooding the liver largely unchecked. A chronic surplus drives fatty liver and is mechanistically linked to MASLD. Tracer studies (using ¹³C-acetate or deuterium water) estimate DNL makes up roughly 15 to 25% of liver triglycerides in MASLD patients. That is modest in absolute terms. But DNL also makes malonyl-CoA, which blocks fat-burning in the mitochondria (via CPT-1), amplifying the fat buildup. A controlled feeding study (Schwarz et al., 2017, 41 obese children, each their own control) is telling. Swapping dietary sugar for starch for nine days cut liver fat, DNL, and fasting insulin, without changing calories. That points to a causal role for sugar-driven DNL in childhood fatty liver, not just an association. Still, the evidence leans on short-term feeding studies and rodents; long-term randomized data in adults with established MASLD are lacking.

Last reviewed: June 22, 2026

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