蛋白质稳态调节肥胖相关衰老的功能研究

Obesity is defined as fat accumulations in either the adipose tissues or non-adipose tissues, which is known to be associated with metabolic diseases such as fat liver, hypertension and atherosclerosis, and to accelerate the process of aging. However, it remains unknown how age-related fat accumulation (age-related obesity) is regulated and why the aging process is accelerated in the obese individuals (obesity-related aging). Recently, our lab has shown that the histone deacetylase HDAC6 and the chaperone molecule dHsc4 regulate age-related fat accumulation through maintaining the proteostasis of PLIN2 (Yan et al., Nature Cell Biol., 2016, revised). These findings, for the first time, demonstrate that proteostasis is linked to age-related obesity; and that improved proteostasis in the obese flies can extend the lifespan of such flies, implying that there is a link between proteostasis and obesity-related aging. In this grant proposal, we intend to study how proteostasis is involved in obesity-related aging and our study will potentially shed new light onto the drug target design for obesity-related diseases.

肥胖是指人体内脂肪在脂肪组织或非脂肪组织中过多堆积的现象。肥胖不仅可能引起各种代谢相关的疾病，如脂肪肝和冠心病等，还能加速机体组织的衰老。目前尚不清楚在个体衰老过程中的肥胖(衰老相关肥胖)是如何发生的，也不清楚肥胖是如何引起机体组织的衰老及功能衰竭(肥胖相关衰老)。近期，我们实验室在果蝇中发现组蛋白去乙酰化酶HDAC6与蛋白分子伴侣dHsc4共同调节脂滴表面蛋白PLIN2的蛋白质稳态，从而参与调节衰老相关肥胖过程(Yan et al., Nature Cell Biol., 2016, 已修回)。该研究首次建立了蛋白质稳态和衰老相关肥胖的关系；同时该研究还发现肥胖果蝇的蛋白质稳态失衡显著加剧，改善蛋白质稳态可以增加肥胖果蝇的寿命，提示蛋白质稳态与肥胖相关衰老可能存在的内在联系。因此，该申请计划深入研究蛋白质稳态如何参与肥胖相关衰老过程，研究结果有可能为肥胖并发症的预防和治疗提供药物靶点。

我们运用遗传、细胞、分子生物学技术以果蝇为模型，证明dHDAC6通过调节选择性自噬参与绛色细胞（oenocytes）脂滴代谢在应对饥饿过程中的作用。dHDAC6调节p62/SQSTM1介导的聚集体（aggresome）的形成，说明选择性自噬是脂滴识别与降解必须的。dHDAC6功能缺失导致饥饿引起的脂肪变性（steatosis）。我们的研究揭示了选择性自噬可能与压力引起的脂肪堆积相关的疾病有关。我们还发现dHDAC6 可以调节抑制衰老相关的过度脂肪堆积，其作用机理是通过维持PLIN2 的蛋白稳态。年龄相关的脂肪堆积可以引起合度疾病比如肥胖、糖尿病以及肿瘤等。我们用果蝇为模型，鉴定出dHDAC6 是一个衰老相关的过度脂肪堆积的抑制因子。dHDAC6 缺失引起脂堆积、脂分子组成失衡、果蝇衰老加速等表型。减少PLIN2 的剂量有助于缓解这些表型。进一步的分子机制研究揭示出dHDAC6 通过调节对dHsc4 的乙酰化水平而调节它的活性，是的它的底物PLIN2 的蛋白质稳态得以维持。最终控制脂滴的异位积累。这一发现为揭示脂肪肝的机制和干预提供了重要线索。