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

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Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-10-01 , DOI: 10.1016/j.cmet.2019.09.003
Samir Softic ₁ , Jesse G Meyer ₂ , Guo-Xiao Wang ₃ , Manoj K Gupta ₄ , Thiago M Batista ₃ , Hans P M M Lauritzen ₃ , Shiho Fujisaka ₅ , Dolors Serra ₆ , Laura Herrero ₆ , Jennifer Willoughby ₇ , Kevin Fitzgerald ₇ , Olga Ilkayeva ₈ , Christopher B Newgard ₈ , Bradford W Gibson ₂ , Birgit Schilling ₂ , David E Cohen ₉ , C Ronald Kahn ₃

Affiliation

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.
Chemistry & Mass Spectrometry, Buck Institute for Research on Aging, Novato, CA 94945, USA.
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
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.
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.
Alnylam Pharmaceuticals Inc., Cambridge, MA 021428, USA.
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.
Division of Gastroenterology and Hepatology, Weill Cornell Medical College New York, New York, NY 10021, USA.

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.

中文翻译：

膳食糖通过线粒体蛋白的转录和翻译后修饰改变肝脏脂肪酸氧化。

膳食糖、果糖和葡萄糖可促进肝脏从头脂肪生成，并改变高脂饮食 (HFD) 对胰岛素抵抗发展的影响。在这里，我们表明，HFD 中的果糖和葡萄糖补充对肝线粒体功能和脂肪酸氧化产生不同的影响。这是通过三个不同的调节节点介导的，包括对丙二酰辅酶A水平的不同影响、对线粒体大小/蛋白质丰度的影响以及线粒体蛋白质的乙酰化。 HFD 和 HFD 加果糖喂养的小鼠降低了 CTP1a 活性（脂肪酸氧化的限速酶），而果糖代谢的敲低则增加了 CPT1a 及其酰基肉碱产物。此外，补充果糖的 HFD 会导致 ACADL 和 CPT1a 乙酰化增加，这与脂肪代谢减少有关。总之，膳食果糖（而不是葡萄糖）补充 HFD 会损害线粒体大小、功能和蛋白质乙酰化，导致脂肪酸氧化减少和代谢失调。

更新日期：2019-10-02

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