The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accumulation and protein kinase C activity in male rat liver.

The Journal of Physiology Pub Date : 2022-09-01 Epub Date: 2022-09-04 DOI:10.1113/JP283552
Shailee Jani, Daniel Da Eira, Mateja Stefanovic, Rolando B Ceddia
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引用次数: 7

Abstract

Obesity-associated insulin resistance plays a major role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramide content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched diet (HFS) or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C-ε activity, but markedly increased liver ceramide content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4 and Il6), and shifted substrate away from de novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. KEY POINTS: The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and non-alcoholic fatty liver disease (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver. The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver. The KD also promoted the production of beneficial very long-chain ceramides instead of potentially harmful long-chain ceramides. Through multiple mechanisms, the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.

生酮饮食通过减少雄性大鼠肝脏脂肪生成、二酰基甘油积累和蛋白激酶C活性来预防脂肪变性和胰岛素抵抗。
肥胖相关的胰岛素抵抗在非酒精性脂肪性肝病(NAFLD)的发病机制中起重要作用。二酰基甘油(DAG)、神经酰胺和炎症的积累是导致NAFLD的关键因素。近年来,生酮饮食(KD)已成为治疗NAFLD和其他肥胖相关代谢紊乱的有效非药物干预手段。目前尚不清楚KD如何影响DAG和神经酰胺含量以及肝脏中的胰岛素敏感性。因此,本研究旨在评估这些变量,以及暴露于以下饮食之一8周的大鼠肝脏中的葡萄糖和脂肪代谢和炎症标志物:标准食物(SC),致肥性高脂肪,富含蔗糖的饮食(HFS)或KD。尽管脂肪含量高于高脂饮食,但KD没有引起脂肪变性,并保留了肝脏胰岛素信号。KD降低了DAG含量和蛋白激酶C-ε活性,但显著提高了肝神经酰胺含量。然而,KD增加了神经酰胺合成酶2 (CerS2)的表达,抑制了CerS6的表达,促进了有益的极长链神经酰胺的产生,而不是有害的长链神经酰胺的产生。KD还增强了参与线粒体生物发生和脂肪酸氧化的关键基因(Pgc-1α和Fgf21)的肝脏表达,抑制了炎症基因(Tnfα, Nf-kb, Tlr4和Il6),并使底物远离了新生脂肪生成。因此,通过多种机制,KD在肝脏中发挥抗脂肪生成和胰岛素增敏作用,这支持使用这种饮食干预来治疗NAFLD。二酰基甘油(DAG)、神经酰胺和炎症的积累是导致胰岛素抵抗和非酒精性脂肪性肝病(NAFLD)的关键因素。本研究提供的证据表明,富含脂肪和缺乏碳水化合物的生酮饮食(KD)降低了DAG含量,并保留了肝脏中的胰岛素信号。KD通过增强参与线粒体生物发生和肝脏脂肪酸氧化的基因,将代谢从脂肪生成转移。KD还促进了有益的极长链神经酰胺的产生,而不是潜在的有害的长链神经酰胺。通过多种机制,KD在肝脏中发挥抗脂肪生成和胰岛素增敏作用,这支持使用这种饮食干预来治疗NAFLD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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