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An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans

Journal article
Authors A. Mardinoglu
Hao Wu
Elias Björnson
C. Zhang
A. Hakkarainen
S. M. Rasanen
S. Lee
Rosellina Margherita Mancina
Mattias Bergentall
K. H. Pietilainen
S. Soderlund
N. Matikainen
Marcus Ståhlman
Per-Olof Bergh
Martin Adiels
B. D. Piening
M. Graner
N. Lundbom
Kevin Jon Williams
Stefano Romeo
J. Nielsen
M. Snyder
M. Uhlen
Göran Bergström
Rosie Perkins
Hanns-Ulrich Marschall
Fredrik Bäckhed
M. R. Taskinen
Jan Borén
Published in Cell Metabolism
Volume 27
Issue 3
Pages 559–571.e5
ISSN 1550-4131
Publication year 2018
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 559–571.e5
Language en
Keywords nonalcoholic fatty liver, growth-factor 21, very-low-carbohydrate, insulin-resistance, weight-loss, lipid-metabolism, gut microbiota, ppar-alpha, folate-deficiency, glutathione metabolism, Cell Biology, Endocrinology & Metabolism
Subject categories Endocrinology and Diabetes, Medical cell biology


A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum beta-hydroxybutyrate concentrations, reflecting increased mitochondrial beta-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.

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