Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.

Steven Zhao, Cholsoon Jang, Joyce Liu, Kahealani Uehara, Michael Gilbert, Luke Izzo, Xianfeng Zeng, Sophie Trefely, Sully Fernandez, Alessandro Carrer, Katelyn D Miller, Zachary T Schug, Nathaniel W Snyder, Terence P Gade, Paul M Titchenell, Joshua D Rabinowitz, Kathryn E Wellen

Journal: Nature 2020;579(7800):586-591

PMID: 32214246

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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 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.

Address: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Cell & Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Biochemistry & Molecular Biophysics Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Biochemistry & Molecular Biophysics Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Veneto Institute of Molecular Medicine (VIMM), Padua, Italy.; Molecular and Cellular Oncogenesis, Wistar Institute, Philadelphia, PA, USA.; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].

DOI: 10.1038/s41586-020-2101-7

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MeSH Terms: ATP Citrate (pro-S)-Lyase, Acetate-CoA Ligase, Acetates, Acetyl Coenzyme A, Animals, Citric Acid, Dietary Sugars, Fatty Acids, Fructose, Gastrointestinal Microbiome, Gene Expression Regulation, Hepatocytes, Isotope Labeling, Lipogenesis, Liver, Male, Mice, Substrate Specificity