Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.

TitleDietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
Publication TypeJournal Article
Year of Publication2020
AuthorsZhao, S, Jang, C, Liu, J, Uehara, K, Gilbert, M, Izzo, L, Zeng, X, Trefely, S, Fernandez, S, Carrer, A, Miller, KD, Schug, ZT, Snyder, NW, Gade, TP, Titchenell, PM, Rabinowitz, JD, Wellen, KE
JournalNature
Volume579
Issue7800
Pagination586-591
Date Published2020 03
ISSN1476-4687
KeywordsAcetate-CoA Ligase, Acetates, Acetyl Coenzyme A, Animals, ATP Citrate (pro-S)-Lyase, Citric Acid, Dietary Sugars, Fatty Acids, Fructose, Gastrointestinal Microbiome, Gene Expression Regulation, Hepatocytes, Isotope Labeling, Lipogenesis, Liver, Male, Mice, Substrate Specificity
Abstract

<p>Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease. Fructose intake triggers de novo lipogenesis in the liver, 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 carbohydrates. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases. 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 microbiota, and this supplies lipogenic acetyl-CoA independently of ACLY. 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.</p>

DOI10.1038/s41586-020-2101-7
Alternate JournalNature
PubMed ID32214246
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
K01 DK111715 / DK / NIDDK NIH HHS / United States
T32 CA009171 / CA / NCI NIH HHS / United States
T32 DK007314 / DK / NIDDK NIH HHS / United States