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Cell Metab. 2019 Oct 1;30(4):735-753.e4. doi: 10.1016/j.cmet.2019.09.003.

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

Author information

1
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Hepatology, Nutrition, Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children's Hospital, Lexington, KY 40506, USA. Electronic address: samir.softic@uky.edu.
2
Chemistry & Mass Spectrometry, Buck Institute for Research on Aging, Novato, CA 94945, USA.
3
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
4
Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
5
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; First Department of Internal Medicine, University of Toyama, Toyama 930-0194, Japan.
6
School of Pharmacy, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain.
7
Alnylam Pharmaceuticals Inc., Cambridge, MA 021428, USA.
8
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology & Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USA.
9
Division of Gastroenterology and Hepatology, Weill Cornell Medical College New York, New York, NY 10021, USA.
10
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: c.ronald.kahn@joslin.harvard.edu.

Abstract

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.

KEYWORDS:

acetylation; fatty acid oxidation; fatty liver disease; fructose; glucose; ketohexokinase; mass spectrometry; mitochondria; obesity; sugar

PMID:
31577934
DOI:
10.1016/j.cmet.2019.09.003

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