The patatin-like phospholipase domain containing protein 7 facilitates VLDL secretion by modulating ApoE stability.
The patatin-like phospholipase domain containing protein 7 facilitates VLDL secretion by modulating ApoE stability.
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含有蛋白 7 的 patatin 样磷脂酶结构域通过调节 ApoE 稳定性促进 VLDL 分泌
DOI：
10.1002/hep.31161
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发表时间：
2020
期刊：
影响因子：
13.5
通讯作者：
Li John Zhong
中科院分区：
文献类型：
--
作者：
Wang Xiuyun;Guo Min;Wang Qian;Wang Qingjie;Zuo Shasha;Zhang Xu;Tong Hui;Chen Jizheng;Wang Huiming;Chen Xiaowei;Guo Junyuan;Su Xiong;Liang Hui;Zhou Hongwen;Li John Zhong
研究背景与目的肝脏极低密度脂蛋白（VLDL）分泌的调节对脂代谢至关重要，而脂代谢的病理状态与脂肪肝和脂肪肝中的血脂异常有关。大量证据表明载脂蛋白E（ApoE）与肝脏VLDL的分泌密切相关。在这里，我们报告了马铃薯糖样磷脂酶结构域蛋白7（PNPLA 7）的表达被肝脂肪变性强烈诱导，并且与人类受试者中的血浆三酰甘油（TAG）水平正相关，而PNPLA 7在肝VLDL分泌中的作用尚不清楚。肝脏PNPLA 7表达的缺乏导致VLDL分泌减少，伴随着肝脏脂质积累增加和肝脏ApoE表达减少。此外，敲低db/db小鼠肝脏中的PNPLA 7也导致血浆TAG水平显著降低，但加重肝脂肪变性。重要的是，我们观察到PNPLA 7与ApoE相互作用，并推测在内质网的网站。从机制上讲，我们已经证明PNPLA 7可以调节多聚泛素化和蛋白酶体介导的ApoE降解。结论PNPLA 7通过与ApoE相互作用调节ApoE的稳定性，从而调节VLDL的分泌。
Background and AimsThe regulation of hepatic very‐low‐density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin‐like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown.Approach and ResultsHerein, with genetic manipulation in the mice, the deficiency of hepatic PNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of thedb/dbmice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal‐mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL‐TAG metabolism in PNPLA7‐knockdown primary hepatocytes.ConclusionPNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE.