PNPLA7调控脂肪细胞线粒体自噬在脂肪-肝脏代谢交流中的作用及机制

Mitochondrial homeostasis plays an important role in maintaining thermogenic function of brown and beige adipocytes. Dysregulation of mitochondrial homeostasis in adipocytes cause serious metabolic disorders, but the effect of the dysregulation of adipocyte mitochondrial homeostasis on heaptic glucose and lipid metabolism is still not clear. In recent years, the metabolic communication between liver and adipose tissue is emerging as critical contributor to nutrient and energy homeostasis. Our previous study found that overexpression of PNPLA7 in adipose tissue enhances mitophagy of adipocytes, leading to impaired mitochondrial function. However, PNPLA7 transgenic mice were resistant to HFD induced hepatic lipid accumulation and have low blood glucose levels, but the underlying mechanism is unclear. In this study, we proposed to investigate the precise molecular mechanism of PNPLA7 on regulating adipocytes mitophagy by using PNPLA7 adipose tissue transgenic mice, the whole body and fat tissue specific gene knockout mice and primary cell as a model system. We will therefore figure out the role and mechanism of PNPLA7-regulated mitophagy of adipocytes on metabolic cross-talk between liver and adipose tissue. Finally, uncover the physiological relevance of mitochondrial homeostasis of adipocytes on hepatic energy metabolism.

维持线粒体稳态对棕色和米色脂肪细胞发挥正常的产热功能具有重要作用。脂肪细胞线粒体稳态失衡可以导致严重的能量代谢障碍。但是脂肪细胞线粒体稳态失衡对肝脏糖脂代谢的影响尚不清楚。近年来肝脏和脂肪组织器官间的交流正成为营养和能量代谢研究的热点。我们前期研究发现，在脂肪组织过表达PNPLA7可以增强小鼠脂肪细胞线粒体自噬从而导致线粒体功能受损，但是却可以抵抗高脂饮食诱导的肝脏脂肪堆积和降低血糖水平。但是具体的机制尚不清楚。我们拟在此基础上借助PNPLA7脂肪组织特异性转基因小鼠、全身及脂肪组织特异性基因敲除小鼠和原代细胞系统，从PNPLA7对脂肪细胞线粒体自噬调控入手，明确PNPLA7调控脂肪细胞线粒体自噬的具体机制，揭示PNPLA7是如何通过调节脂肪细胞线粒体稳态从而调控肝脏的糖脂代谢的生理功能。最终阐明脂肪细胞线粒体稳态对脂肪-肝脏代谢交流的作用及分子机制。

维持线粒体稳态对棕色和米色脂肪细胞发挥正常的产热功能具有重要作用，脂肪细胞线粒体稳态失衡可以导致严重的能量代谢障碍，近年来脂肪组织和肝脏器官间的交流正成为营养和能量代谢研究的热点，但是脂肪细胞线粒体稳态失衡对肝脏糖脂代谢的影响尚不清楚。在本项目执行期间：（1）我们发现了新的产热调控因子PNPLA7调控白色脂肪棕色化的分子机制。（2）初步阐明了脂肪细胞中线粒体自噬的失衡影响了脂肪细胞分泌的外泌体调节肝脏脂质堆积，为脂肪-肝脏器官间交流的分子机制提供了新的思路。经过本项目的实施，明确回答了提出的科学问题，共发表标志本基金号科技论文6篇，其中SCI论文5篇，均发表在一流国际期刊上，包括Hepatology（2020）、Diabetes（2022）、Am. J. Physiol (2022)、Metabolism（2021）、Cell Metabolism（2021）。这些研究成果对我们正确认识脂肪-肝脏互作有重要意义。