Title | Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Zhao, 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 |
Journal | Nature |
Volume | 579 |
Issue | 7800 |
Pagination | 586-591 |
Date Published | 2020 Mar |
ISSN | 1476-4687 |
Keywords | Acetate-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> |
DOI | 10.1038/s41586-020-2101-7 |
Alternate Journal | Nature |
PubMed ID | 32214246 |
PubMed Central ID | PMC7416516 |
Grant List | DP1 DK113643 / DK / NIDDK NIH HHS / United States P30 CA010815 / CA / NCI NIH HHS / United States R01 GM132261 / GM / NIGMS NIH HHS / United States R01 CA174761 / CA / NCI NIH HHS / United States R03 HD092630 / HD / NICHD NIH HHS / United States F99 CA222741 / CA / NCI NIH HHS / United States T32 GM007229 / GM / NIGMS NIH HHS / United States R01 DK116005 / DK / NIDDK NIH HHS / United States T32 CA009171 / CA / NCI NIH HHS / United States T32 AR053461 / AR / NIAMS NIH HHS / United States K01 DK111715 / DK / NIDDK NIH HHS / United States K12 GM081259 / GM / NIGMS NIH HHS / United States R01 CA228339 / CA / NCI NIH HHS / United States T32 DK007314 / DK / NIDDK NIH HHS / United States P30 DK019525 / DK / NIDDK NIH HHS / United States |