Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD.
Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD.
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DOI：
10.1096/fj.202001495r
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Sunny NE
中科院分区：
文献类型：
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作者：
Muyyarikkandy MS;McLeod M;Maguire M;Mahar R;Kattapuram N;Zhang C;Surugihalli C;Muralidaran V;Vavilikolanu K;Mathews CE;Merritt ME;Sunny NE
非酒精性脂肪性肝病（NAFLD）期间的线粒体适应包括生酮通量和持续三羧酸（TCA）循环活性的重塑，这与氧化应激的发生同时发生。超过70%的肥胖人群患有NAFLD，生酮饮食是常见的减肥策略。然而，生酮饮食对缓解NAFLD的有效性仍不清楚。我们假设慢性生酮会加重NAFLD期间的代谢功能障碍和氧化应激。通过替代碳水化合物卡路里（生酮），将小鼠（C57 BL/6）饲养（16周）在补充有1.5X支链氨基酸（BCAA）的低脂、高脂或高脂饮食中。生酮饮食诱导肝脏脂质氧化和生酮，并通过TCA循环的各个步骤产生多方面的流量变化。由生酮饮食引起的较高的肝脏氧化通量率导致较低的新生脂肪生成率。有趣的是，这种代谢重塑并没有改善胰岛素抵抗，而是诱导了肝脏中的纤维化基因和炎症。在慢性“生酮环境”下，肝细胞将更多的乙酰辅酶A从脂肪生成转向生酮和TCA循环，这是一种可以加速氧化应激和炎症的环境。总之，肥胖和NAFLD期间长期暴露于生酮环境可能会加重肝线粒体功能障碍。
Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include remodeling of ketogenic flux and sustained tricarboxylic acid (TCA) cycle activity, which are concurrent to onset of oxidative stress. Over 70% of obese humans have NAFLD and ketogenic diets are common weight loss strategies. However, the effectiveness of ketogenic diets toward alleviating NAFLD remains unclear. We hypothesized that chronic ketogenesis will worsen metabolic dysfunction and oxidative stress during NAFLD. Mice (C57BL/6) were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet supplemented with 1.5X branched chain amino acids (BCAAs) by replacing carbohydrate calories (ketogenic). The ketogenic diet induced hepatic lipid oxidation and ketogenesis, and produced multifaceted changes in flux through the individual steps of the TCA cycle. Higher rates of hepatic oxidative fluxes fueled by the ketogenic diet paralleled lower rates of de novo lipogenesis. Interestingly, this metabolic remodeling did not improve insulin resistance, but induced fibrogenic genes and inflammation in the liver. Under a chronic “ketogenic environment,” the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle, a milieu which can hasten oxidative stress and inflammation. In summary, chronic exposure to ketogenic environment during obesity and NAFLD has the potential to aggravate hepatic mitochondrial dysfunction.