衰老过程中伴侣介导的自噬失调通过 NCoR1 的积累损害肝脏脂肪酸氧化。
Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1.
机构信息
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Division of Life Science, Korea Polar Research Institute, Incheon 21990, Republic of Korea.
出版信息
Mol Metab. 2023 Oct;76:101784. doi: 10.1016/j.molmet.2023.101784. Epub 2023 Jul 29.
OBJECTIVE
Alterations in lipid metabolism are associated with aging and age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process involved in specific protein degradation. Heat shock cognate 71 kDa protein (Hsc70) recognizes cytosolic proteins with KFERQ motif and allows them to enter the lysosome via lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A). CMA deficiency is associated with dysregulated lipid metabolism in the liver. In this study, we examined the effect of CMA on lipid metabolism in the aged liver.
METHODS
12-week-old and 88-week-old mice were employed to assess the effect of aging on hepatic CMA activity. We generated CMA-deficient mouse primary hepatocytes using siRNA for Lamp2a and liver-specific LAMP2A knockdown mice via adeno-associated viruses expressing short hairpin RNAs to investigate the influence of CMA on lipid metabolism.
RESULTS
We noted aging-induced progression toward fatty liver and a decrease in LAMP2A levels in total protein and lysosomes. The expression of genes associated with fatty acid oxidation was markedly downregulated in the aged liver, as verified in CMA-deficient mouse primary hepatocytes. In addition, the aged liver accumulated nuclear receptor corepressor 1 (NCoR1), a negative regulator of peroxisome proliferator-activated receptor α (PPARα). We found that Hsc70 binds to NCoR1 via the KFERQ motif. Lamp2a siRNA treatment accumulated NCoR1 and decreased the fatty acid oxidation rate. Pharmacological activation of CMA by AR7 treatment increased LAMP2A expression, leading to NCoR1 degradation. A liver-specific LAMP2A knockdown via adeno-associated viruses expressing short hairpin RNAs caused NCoR1 accumulation, inactivated PPARα, downregulated the expression of fatty acid oxidation-related genes and significantly increased liver triglyceride levels.
CONCLUSIONS
Our results elucidated a novel PPARα regulatory mechanism involving CMA-mediated NCoR1 degradation during aging. These findings demonstrate that CMA dysregulation is crucial for the progression of aging-related fatty liver diseases.
目的
脂质代谢的改变与衰老和衰老相关疾病有关。伴侣介导的自噬（CMA）是一种溶酶体依赖性过程，参与特定蛋白质的降解。热休克同源 71kDa 蛋白（Hsc70）识别具有 KFERQ 基序的胞质蛋白，并允许它们通过溶酶体相关膜糖蛋白 2 同工型 A（LAMP2A）进入溶酶体。CMA 缺陷与肝脏中脂质代谢失调有关。在这项研究中，我们研究了 CMA 对衰老肝脏中脂质代谢的影响。
方法
使用 12 周龄和 88 周龄的小鼠评估衰老对肝 CMA 活性的影响。我们使用 Lamp2a 的 siRNA 生成 CMA 缺陷型小鼠原代肝细胞，并通过表达短发夹 RNA 的腺相关病毒生成肝特异性 LAMP2A 敲低小鼠，以研究 CMA 对脂质代谢的影响。
结果
我们发现衰老引起的脂肪肝进展和总蛋白和溶酶体中 LAMP2A 水平降低。衰老肝脏中与脂肪酸氧化相关的基因表达明显下调，在 CMA 缺陷型小鼠原代肝细胞中得到验证。此外，衰老的肝脏积累了核受体共抑制因子 1（NCoR1），这是过氧化物酶体增殖物激活受体 α（PPARα）的负调节剂。我们发现 Hsc70 通过 KFERQ 基序与 NCoR1 结合。Lamp2a siRNA 处理会积累 NCoR1 并降低脂肪酸氧化速率。用 AR7 治疗药物激活 CMA 可增加 LAMP2A 表达，导致 NCoR1 降解。通过表达短发夹 RNA 的腺相关病毒进行肝特异性 LAMP2A 敲低会导致 NCoR1 积累、激活 PPARα、下调与脂肪酸氧化相关的基因表达，并显著增加肝脏甘油三酯水平。
结论
我们的结果阐明了一种新的 PPARα 调节机制，涉及衰老过程中 CMA 介导的 NCoR1 降解。这些发现表明 CMA 失调对于衰老相关脂肪性肝病的进展至关重要。
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