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.
Cell Metab. 2019 Oct 1;30(4):735-753.e4. doi: 10.1016/j.cmet.2019.09.003.
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.
饮食中的糖，果糖和葡萄糖，可促进肝脏从头合成脂肪，并改变高脂肪饮食（HFD）对胰岛素抵抗发展的影响。在这里，我们表明，HFD 中果糖和葡萄糖的补充对肝脏线粒体功能和脂肪酸氧化有不同的影响。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 水平的差异影响，对线粒体大小/蛋白质丰度的影响以及对线粒体蛋白的乙酰化作用。HFD 和 HFD 加果糖喂养的小鼠的 CTP1a 活性降低，该酶是脂肪酸氧化的限速酶，而果糖代谢的敲低则增加 CPT1a 及其酰基辅酶 A 产物。此外，补充果糖的 HFD 导致 ACADL 和 CPT1a 的乙酰化增加，这与脂肪代谢减少有关。总之，HFD 中添加膳食果糖而非葡萄糖会损害线粒体的大小，功能和蛋白质乙酰化，从而导致脂肪酸氧化减少和代谢失调的发展。
