PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.
PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.
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DOI：
10.1016/j.isci.2022.105612
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发表时间：
2022-12-22
期刊：
影响因子：
5.8
通讯作者：
Shirane, Michiko
中科院分区：
文献类型：
--
作者：
Morita, Keiko;Wada, Mariko;Nakatani, Kohta;Matsumoto, Yuki;Hayashi, Nahoki;Yamahata, Ikuko;Mitsunari, Kotone;Mukae, Nagi;Takahashi, Masatomo;Izumi, Yoshihiro;Bamba, Takeshi;Shirane, Michiko
血脂异常包括大脑中胆固醇酯（CEs）的积累与神经系统疾病有关，尽管其潜在机制尚不清楚。PDZD8是一种Rab7效应蛋白，在内质网（ER）和Rab7阳性细胞器之间传递脂质，从而促进内溶酶体的成熟，并有助于维持神经元的完整性。本研究表明，由于脂质吞噬受损，pdzd8缺陷小鼠的大脑中CEs积累。这种CE积累不受饮食的影响，暗示细胞内脂质代谢存在缺陷。虽然胆固醇合成正常，但在pdzd8缺陷小鼠的大脑中，脂滴（ld）的降解存在缺陷。PDZD8可能介导内质网和rab7阳性细胞器之间胆固醇和磷脂酰丝氨酸的交换，促进含ce的ld与溶酶体融合降解。因此，我们的研究结果表明，PDZD8通过脂质吞噬促进大脑中ce的清除，PDZD8的这一作用可能有助于大脑功能。PDZD8介导内质网和Rab7+细胞器之间PS和胆固醇的交换PDZD8促进溶酶体与ld的成熟和融合，导致脂质噬噬PDZD8缺乏导致CE积累，进而导致脑内血脂异常PDZD8通过清除CE参与脑功能；分子生物学;神经科学。
Dyslipidemia including the accumulation of cholesteryl esters (CEs) in the brain is associated with neurological disorders, although the underlying mechanism has been unclear. PDZD8, a Rab7 effector protein, transfers lipids between endoplasmic reticulum (ER) and Rab7-positive organelles and thereby promotes endolysosome maturation and contributes to the maintenance of neuronal integrity. Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy. This CE accumulation was not affected by diet, implicating a defect in intracellular lipid metabolism. Whereas cholesterol synthesis appeared normal, degradation of lipid droplets (LDs) was defective, in the brain of PDZD8-deficient mice. PDZD8 may mediate the exchange of cholesterol and phosphatidylserine between ER and Rab7-positive organelles to promote the fusion of CE-containing LDs with lysosomes for their degradation. Our results thus suggest that PDZD8 promotes clearance of CEs from the brain by lipophagy, with this role of PDZD8 likely contributing to brain function. PDZD8 mediates the exchange of PS and cholesterol between ER and Rab7+ organelles PDZD8 promotes the maturation and fusion of lysosomes with LDs, leading to lipophagy Deficiency of PDZD8 results in CE accumulation and consequent dyslipidemia in brain PDZD8 thus contributes to brain function through the clearance of CEs Biological sciences; Molecular biology; Neuroscience.
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影响因子：
4.6
作者：
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通讯作者：
Im YJ
影响因子：
11.8
作者：
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DOI：
10.1083/jcb.201609033
发表时间：
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期刊：
The Journal of cell biology
影响因子：
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Reid E
影响因子：
6.1
作者：
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DOI：
10.1126/science.aah6171
发表时间：
2017-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
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Lees JA;Messa M;Sun EW;Wheeler H;Torta F;Wenk MR;De Camilli P;Reinisch KM
通讯作者：
Reinisch KM