Objective

Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.

Methods

Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches. Mechanistic studies of pioglitazone action were performed in isolated primary hepatocytes, whilst molecular hepatic lipid species were profiled using shotgun lipidomics.

Results

Livers from obese, insulin-resistant mice displayed augmented mitochondrial content and increased tricarboxylic acid cycle (TCA) cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPARγ activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides, or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization.

Conclusion

Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.

中文翻译：

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胰岛素抵抗与非酒精性脂肪性肝病中的肝线粒体重塑在机制上有关

客观的

胰岛素抵抗和肝线粒体功能改变是 2 型糖尿病 (T2D) 和非酒精性脂肪性肝病 (NAFLD) 的核心特征，但这些过程在疾病进展中的病因学作用仍不清楚。在这里，我们研究了胰岛素抵抗、线粒体重塑和肝脏脂质积累之间的分子联系。

方法

使用放射性标记示踪剂和稳定同位素 NMR 方法的组合，在野生型、肥胖 (ob/ob) 和吡格列酮治疗的肥胖小鼠中测定肝胰岛素敏感性、内源性葡萄糖产生和线粒体代谢通量。在分离的原代肝细胞中进行吡格列酮作用的机制研究，同时使用鸟枪脂质组学分析分子肝脂质种类。

结果

肥胖、胰岛素抵抗小鼠的肝脏线粒体含量增加，三羧酸循环 (TCA) 循环和丙酮酸脱氢酶 (PDH) 活性增加。用吡格列酮致敏的胰岛素通过依赖于分离的原代肝细胞中 PPARγ 活性的变构（细胞内丙酮酸可用性）和共价（PDK4 和 PDP2）机制减轻了丙酮酸驱动的 TCA 循环活性和 PDH 激活。吡格列酮治疗后线粒体功能的改善与肝脏甘油三酯、二酰基甘油酯或脂肪酸的变化完全无关。相反，我们强调了线粒体磷脂心磷脂的作用，该心磷脂在肥胖小鼠的肝脏中经历了病理性重塑，并被胰岛素敏化逆转。

结论

我们的研究结果确定了 T2D 和 NAFLD 的可靶向线粒体特征，并强调了胰岛素敏化在管理肥胖相关疾病临床负担方面的益处。