한빛사논문
Steven Zhao1,2,3,12, Cholsoon Jang4,12, Joyce Liu1,2,5, Kahealani Uehara5,6,7, Michael Gilbert1,2,5, Luke Izzo1,2,3, Xianfeng Zeng4, Sophie Trefely1,2,8, Sully Fernandez1,2, Alessandro Carrer1,2,11, Katelyn D. Miller9, Zachary T. Schug9, Nathaniel W. Snyder8, Terence P. Gade1,10, Paul M. Titchenell6,7, Joshua D. Rabinowitz4 & Kathryn E. Wellen1,2,7,*
1Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
2Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
3Cell & Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
4Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
5Biochemistry & Molecular Biophysics Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
6Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
7Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
8Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
9Molecular and Cellular Oncogenesis, Wistar Institute, Philadelphia, PA, USA.
10Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
11Present address: Veneto Institute of Molecular Medicine (VIMM), Padua, Italy.
12These authors contributed equally
*Corresponding author
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.
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