Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

Nature. 2020 Mar;579(7800):586-591. doi: 10.1038/s41586-020-2101-7. Epub 2020 Mar 18.


Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2-4. Fructose intake triggers de novo lipogenesis in the liver4-6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.

MeSH terms

  • ATP Citrate (pro-S)-Lyase / deficiency
  • ATP Citrate (pro-S)-Lyase / genetics
  • ATP Citrate (pro-S)-Lyase / metabolism
  • Acetate-CoA Ligase / deficiency
  • Acetate-CoA Ligase / genetics
  • Acetate-CoA Ligase / metabolism
  • Acetates / metabolism*
  • Acetyl Coenzyme A / metabolism
  • Animals
  • Citric Acid / metabolism
  • Dietary Sugars / administration & dosage
  • Dietary Sugars / metabolism*
  • Dietary Sugars / pharmacology
  • Fatty Acids / metabolism
  • Fructose / administration & dosage
  • Fructose / metabolism*
  • Fructose / pharmacology
  • Gastrointestinal Microbiome / drug effects
  • Gastrointestinal Microbiome / physiology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Isotope Labeling
  • Lipogenesis* / drug effects
  • Lipogenesis* / genetics
  • Liver / cytology
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Mice
  • Substrate Specificity


  • Acetates
  • Dietary Sugars
  • Fatty Acids
  • Citric Acid
  • Fructose
  • Acetyl Coenzyme A
  • ATP Citrate (pro-S)-Lyase
  • ACSS2 protein, mouse
  • Acetate-CoA Ligase