Objective

Nonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta (PKCβ), a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic PKCβ in energy homeostasis is limited.

Methods

The floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function.

Results

We report that hepatocyte-specific PKCβ deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance.

Conclusions

The above data indicate that hepatocyte PKCβ is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis.

中文翻译：

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肝细胞特异性 PKCβ 缺乏可预防高脂饮食诱导的非酒精性肝脂肪变性

客观的

非酒精性肝脂肪变性，也称为脂肪肝，是肝脏对高脂高热量饮食摄入的一致反应。然而，驱动肝脂肪变性的摄入后信号和机制过程尚不清楚。新数据表明，蛋白激酶 C beta (PKCβ) 是一种脂质敏感激酶，在能量代谢以及对环境和营养刺激的适应中发挥着关键作用。尽管肝脏 PKCβ 对葡萄糖和脂质代谢具有强大的作用，但对肝脏 PKCβ 在能量稳态中的生理作用的了解仍然有限。

方法

建立 floxed-PKCβ 和肝细胞特异性 PKCβ 缺陷小鼠模型，以研究肝细胞 PKCβ 对饮食诱导的肝脂肪变性、脂质代谢和线粒体功能的体内作用。

结果

我们报告说，肝细胞特异性 PKCβ 缺陷可以保护小鼠免受高脂饮食诱导的肝脂肪变性的发展，而不影响体重增加。这种保护与 SREBP-1c 反式激活的减弱和肝线粒体呼吸链的改善有关。脂质组学分析发现，与对照相比，PKCβ 缺陷肝脏中关键的线粒体内膜脂质（心磷脂）显着增加。此外，肝细胞 PKCβ 缺乏对肝脏或全身胰岛素敏感性没有显着影响，支持肝脏脂肪变性和胰岛素抵抗之间的分离。

结论

上述数据表明，肝细胞 PKCβ 是膳食脂质感知的关键焦点，主要通过协调餐后期间的能量利用和脂肪生成，对肝脏中膳食脂质的有效储存至关重要。这些结果强调了肝脏 PKCβ 作为肥胖相关非酒精性肝脂肪变性药物靶点的重要性。