1. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
- Author
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Zhao, Steven, Jang, Cholsoon, Liu, Joyce, Uehara, Kahealani, Gilbert, Michael, Izzo, Luke, Zeng, Xianfeng, Trefely, Sophie, Fernandez, Sully, Carrer, Alessandro, Miller, Katelyn D, Schug, Zachary T, Snyder, Nathaniel W, Gade, Terence P, Titchenell, Paul M, Rabinowitz, Joshua D, and Wellen, Kathryn E
- Subjects
Liver ,Hepatocytes ,Animals ,Mice ,Acetates ,Citric Acid ,Acetyl Coenzyme A ,Acetate-CoA Ligase ,ATP Citrate (pro-S)-Lyase ,Fructose ,Fatty Acids ,Isotope Labeling ,Gene Expression Regulation ,Substrate Specificity ,Male ,Lipogenesis ,Gastrointestinal Microbiome ,Dietary Sugars ,Digestive Diseases ,Liver Disease ,Nutrition ,Obesity ,Oral and gastrointestinal ,General Science & Technology - Abstract
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.
- Published
- 2020