Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins

Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on hepatic mitochondrial function and fatty ac...

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Published inCell metabolism Vol. 30; no. 4; pp. 735 - 753.e4
Main Authors Softic, Samir, Meyer, Jesse G, Wang, Guo-Xiao, Gupta, Manoj K, Batista, Thiago M, Lauritzen, Hans P M M, Fujisaka, Shiho, Serra, Dolors, Herrero, Laura, Willoughby, Jennifer, Fitzgerald, Kevin, Ilkayeva, Olga, Newgard, Christopher B, Gibson, Bradford W, Schilling, Birgit, Cohen, David E, Kahn, C Ronald
Format Journal Article
LanguageEnglish
Published United States 01.10.2019
Subjects
Animals
Cell Line
Diet, High-Fat - adverse effects
Dietary Sugars - adverse effects
Fatty Acids - metabolism
Fructose - adverse effects
Glucose - adverse effects
Lipogenesis
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Obesity - metabolism
Protein Processing, Post-Translational
Transcription, Genetic
acetylation
glucose
mitochondria
fructose
ketohexokinase
mass spectrometry
fatty acid oxidation
sugar
obesity
fatty liver disease
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Summary:Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on hepatic mitochondrial function and fatty acid oxidation. This is mediated via three different nodes of regulation, including differential effects on malonyl-CoA levels, effects on mitochondrial size/protein abundance, and acetylation of mitochondrial proteins. HFD- and HFD plus fructose-fed mice have decreased CTP1a activity, the rate-limiting enzyme of fatty acid oxidation, whereas knockdown of fructose metabolism increases CPT1a and its acylcarnitine products. Furthermore, fructose-supplemented HFD leads to increased acetylation of ACADL and CPT1a, which is associated with decreased fat metabolism. In summary, dietary fructose, but not glucose, supplementation of HFD impairs mitochondrial size, function, and protein acetylation, resulting in decreased fatty acid oxidation and development of metabolic dysregulation.
Bibliography:AUTHOR CONTRIBUTIONS
S.S. designed the experiments, performed the experiments, and wrote the manuscript. G.-X.W., M.K.G., T.M.B., and S.F. helped perform the experiments and edited the manuscript. J.G.M., B.W.G., and B.S. performed mitochondrial proteome and acetylome analysis, generated figures, and wrote the manuscript. O.I. and C.B.N. performed liver metabolomics profiling and D.S. and L.H. measured Cpt1a protein levels and activity in isolated mitochondria and wrote the manuscript. H.P.M.M.L. performed confocal microscopy and edited the manuscript. J.W. and K.F. provided siRNA, helped design the experiments, and edited the manuscript. C.B.N. and D.E.C. helped design experiments, provided mentorship, and edited the manuscript. C.R.K. designed the experiments, provided mentorship, and wrote the manuscript.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2019.09.003