Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University , Wuhan , China.
Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E496-E510. doi: 10.1152/ajpendo.00061.2018. Epub 2018 May 15.
Hepatic metabolic syndrome is associated with inflammation, as inflammation stimulates the reprogramming of nutrient metabolism and hepatic mitochondria-generated acetyl-CoA, but how acetyl-CoA affects the reprogramming of nutrient metabolism, especially glucose and fatty acids, in the condition of inflammation is still unclear. Here, we used an acute inflammation model in which pigs were injected with lipopolysaccharide (LPS) and found that hepatic glycolysis and fatty acid oxidation are both promoted. Acetyl-proteome profiling of LPS-infected pigs liver showed that inflammatory stress exacerbates the acetylation of mitochondrial proteins. Both mitochondrial glutamate oxaloacetate transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2) were acetylated, and the malate-aspartate shuttle (MAS) activity was stimulated to maintain glycolysis. With the use of C-carbon tracing in vitro, acetyl-CoA was found to be mainly supplied by lipid-derived fatty acid oxidation rather than glucose-derived pyruvate oxidative decarboxylation, while glucose was mainly used for lactate production in response to inflammatory stress. The results of the mitochondrial experiment showed that acetyl-CoA directly increases MDH2 and, in turn, the GOT2 acetylation level affects MAS activity. Treatment with palmitate in primary hepatocytes from LPS-injected pigs increased the hepatic production of acetyl-CoA, pyruvate, and lactate; MAS activity; and hepatic MDH2 and GOT2 hyperacetylation, while the deficiency of long-chain acetyl-CoA dehydrogenase resulted in the stabilization of these parameters. These observations suggest that acetyl-CoA produced by fatty acid oxidation promotes MAS activity and glycolysis via nonenzymatic acetylation during the inflammatory stress response.
肝脏代谢综合征与炎症有关，因为炎症会刺激营养代谢和肝脏线粒体产生的乙酰辅酶 A 的重编程，但在炎症状态下，乙酰辅酶 A 如何影响营养代谢（尤其是葡萄糖和脂肪酸）的重编程仍不清楚。在这里，我们使用了一种急性炎症模型，即在猪中注射脂多糖（LPS），结果发现肝脏的糖酵解和脂肪酸氧化都被促进了。LPS 感染猪肝脏的乙酰化蛋白质组分析表明，炎症应激会加剧线粒体蛋白的乙酰化。线粒体谷氨酸草酰乙酸转氨酶 2（GOT2）和苹果酸脱氢酶 2（MDH2）都被乙酰化，而苹果酸天冬氨酸穿梭（MAS）活性被刺激以维持糖酵解。通过体外 C-碳示踪，发现乙酰辅酶 A 主要来自脂质衍生的脂肪酸氧化，而不是葡萄糖衍生的丙酮酸氧化脱羧，而葡萄糖主要用于在炎症应激下产生乳酸。线粒体实验的结果表明，乙酰辅酶 A 直接增加 MDH2，进而 GOT2 的乙酰化水平影响 MAS 活性。用棕榈酸处理 LPS 注射猪的原代肝细胞，增加了肝脏中乙酰辅酶 A、丙酮酸和乳酸的产生；MAS 活性；以及肝 MDH2 和 GOT2 的超乙酰化，而长链乙酰辅酶 A 脱氢酶的缺乏则导致这些参数的稳定。这些观察结果表明，在炎症应激反应中，脂肪酸氧化产生的乙酰辅酶 A 通过非酶促乙酰化作用促进 MAS 活性和糖酵解。
