PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling.
PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling.
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PPDPF 通过抑制 mTOR 信号传导减轻肝脏脂肪变性
DOI：
10.1038/s41467-021-23285-8
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发表时间：
2021-05-24
影响因子：
16.6
通讯作者：
Xie D
中科院分区：
文献类型：
--
作者：
Ma N;Wang YK;Xu S;Ni QZ;Zheng QW;Zhu B;Cao HJ;Jiang H;Zhang FK;Yuan YM;Zhang EB;Chen TW;Xia J;Ding XF;Chen ZH;Zhang XP;Wang K;Cheng SQ;Qiu L;Li ZG;Yu YC;Wang XF;Zhou B;Li JJ;Xie D
非酒精性脂肪性肝病（NAFLD）已成为世界上最流行的慢性肝病，然而，尚无药物治疗这种疾病。因此，寻找有效的治疗靶点进行临床干预是当务之急。在这项研究中，我们发现肝脏特异性敲除PPDPF（PPDPF-LKO）导致32周龄的小鼠模型在普通饲料中自发形成脂肪肝，HFD增强了这一点。机制研究表明PPDPF负调节mTORC 1-S6 K-SREBP 1信号传导。PPDPF干扰Raptor和CUL 4 B-DDB 1（一种E3连接酶复合物）之间的相互作用，从而阻止Raptor的泛素化和激活。因此，肝脏特异性PPDPF过表达有效抑制HFD诱导的mTOR信号传导激活和小鼠肝脏脂肪变性。这些结果表明PPDPF是脂质代谢中mTORC 1信号的调节剂，并且可能是NAFLD的潜在治疗候选者。非酒精性脂肪性肝病（NAFLD）已成为一种常见的慢性肝病，然而，治疗这种疾病的药物仍然缺乏。在这里，作者表明PPDPF通过负调节mTORC 1-S6 K-SREBP 1信号传导抑制肝脂肪变性的发展，这为NAFLD治疗提供了潜在的治疗候选者。
Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD. Non-alcoholic fatty liver disease (NAFLD) has become a prevalent chronic liver disease, however, drugs to treat this disease are still lacking. Here, the authors show that PPDPF inhibits the development of hepatic steatosis by negatively regulating mTORC1-S6K-SREBP1 signaling, which provides a potential therapeutic candidate for NAFLD treatment.
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影响因子：
7.3
作者：
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发表时间：
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影响因子：
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作者：
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