Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
Authors: Cholsoon Jang
Paul M Titchenell
Kahealani Uehara
Nathaniel W Snyder
Katelyn D Miller
Michael Gilbert
Alessandro Carrer
Sully Fernandez
Steven Zhao
Luke Izzo
Kathryn E Wellen
Joyce Liu
Xianfeng Zeng
Terence P Gade
Sophie Trefely
Joshua D Rabinowitz
Zachary T Schug
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: fructose consumption; obesity; non-alcoholic fatty liver disease; de novo lipogenesis; ATP citrate lyase
Affiliations: 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., 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., Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Veneto Institute of Molecular Medicine (VIMM), Padua, Italy., Molecular and Cellular Oncogenesis, Wistar Institute, Philadelphia, PA, USA., Department of Radiology, 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. ., Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. .

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. 

Retracted: No

PubPeer comments:
 I was wondering if the authors could please clarify some points in relation to the measures of DNL. The heavy water (D2O) labelling approach used here is unconventional. Typically, a bolus of D2O (15-20 ul g) is administered to rapidly increase body water enrichment to the desired level (usually somewhere between 2-5%) which is maintained by supplementing D2O (generally 6-8% w v) in the drinking water. This ensures rapid equilibration of deuterium (ie. precursor) enrichment in body water, which is then kept constant for the duration of the labelling period. In this paper, the authors used an approach where drinking water was supplemented with 50% D2O. As a consequence precursor enrichment (ie. 2H in body water) is not steady and is continually changing over time. This is a significant issue and the impact of this approach on the data and its interpretation has not been addressed. Moreover, supplementing with 50% D2O would lead to significant dueteration of body water which could have negative impacts on animal behaviour u2013 eg. It is well known that D2O causes vertigo in humans. So just wondering if these animals exhibited any changes in behaviour that could be consistent with the known side effects of D2O? The way the results are presented is also intriguing u2013 ie. the basal level of D2O labelling is set to 1 and compared with D2O labelling after consumption of fructose:glucose within each genotype. Using the typical D2O labelling approach, the fraction of newly synthesised esterified 16:0 and 18:0 can actually be determined - fraction of newly made = product labelling (precursor labelling x n) where precursor labellingu2009=u2009body water 2H enrichment and nu2009=u2009the number of exchangeable hydrogen atoms (~22 for liver 16:0). Then, through calculation of the esterified 16:0 and 18:0 pool size (ie. using the isotope dilution internal standard method), the absolute amount of newly synthesised esterified 16:0 and 18:0 can be determined. This has been independently detailed and validated by the groups of Marc Hellerstein and Stephen Previs. Why were these standard approaches not used? In addition, it is not clear how serum 2H enrichment was determined. This should be detailed in the methods. Also, the Excel source data for Figure 1B report serum 2H enrichments as a % - is this really % or fractional? In relation to the U13C fructose or glucose approaches to measure DNL, I assume the authors measured labelling in the precursor. Could the authors elaborate on what the precursor was? ,