Sino-French Hoffmann Institute, School of Basic Sciences, Guangzhou Medical University, Dongfengxi Road 195, Guangzhou 510182, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, the Chinese Academy of Sciences, Datun Road 15, Beijing 100101, China.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, the Chinese Academy of Sciences, Datun Road 15, Beijing 100101, China; Department of Chemistry and Biology, National University of Defense Technology, Changsha 410072, China.
Dev Cell. 2017 Oct 9;43(1):99-111.e5. doi: 10.1016/j.devcel.2017.09.001. Epub 2017 Sep 28.
Age-dependent ectopic fat accumulation (EFA) in animals contributes to the progression of tissue aging and diseases such as obesity, diabetes, and cancer. However, the primary causes of age-dependent EFA remain largely elusive. Here, we characterize the occurrence of age-dependent EFA in Drosophila and identify HDAC6, a cytosolic histone deacetylase, as a suppressor of EFA. Loss of HDAC6 leads to significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of the lipid-droplet-resident protein PLIN2. We show that HDAC6 is associated physically with the chaperone protein dHsc4/Hsc70 to maintain the proteostasis of PLIN2. These findings indicate that proteostasis collapse serves as an intrinsic cue to cause age-dependent EFA. Our study suggests that manipulation of proteostasis could be an alternative approach to the treatment of age-related metabolic diseases such as obesity and diabetes.
动物中与年龄相关的异位脂肪积累（EFA）会导致组织衰老和肥胖症、糖尿病和癌症等疾病的进展。然而，与年龄相关的 EFA 的主要原因在很大程度上仍难以捉摸。在这里，我们描述了果蝇中与年龄相关的 EFA 的发生，并确定了细胞质组蛋白去乙酰化酶 HDAC6 是 EFA 的抑制因子。HDAC6 的缺失会导致明显的与年龄相关的 EFA、脂质组成失衡以及高脂肪饮食下动物寿命的缩短。减少脂质滴驻留蛋白 PLIN2 可改善 EFA 和寿命表型。我们表明 HDAC6 与伴侣蛋白 dHsc4/Hsc70 物理相关，以维持 PLIN2 的蛋白质稳态。这些发现表明蛋白质稳态崩溃是导致与年龄相关的 EFA 的内在信号。我们的研究表明，蛋白质稳态的操纵可能是治疗肥胖症和糖尿病等与年龄相关的代谢性疾病的一种替代方法。
