NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes.
NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes.
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NEFA通过调节牛肝细胞PERK信号通路促进自噬体形成
DOI：
10.3390/ani11123400
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发表时间：
2021-11-28
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Huang Y;Zhao C;Liu Y;Kong Y;Tan P;Liu S;Zeng F;Yuan Y;Li X;Liu G;Zhao B;Wang J
负能量平衡会导致大量身体脂肪的动员。脂肪分解产生的大量非酯化脂肪酸（NEFA）不仅可用于肝脏中β-氧化产生能量，而且还可作为脂质代谢的潜在调节剂。本研究为NEFA通过蛋白激酶R样内质网激酶（PERK）信号通路激活肝细胞自噬提供了证据。自噬通过促进细胞内脂质的分解而促进脂质代谢。这些研究结果使更好地了解能量的再分配和利用在围产期的奶牛。围产期奶牛能量负平衡（NEB）引起的血浆非酯化脂肪酸（NEFA）浓度异常升高，对奶牛肝脏产生显著的代谢应激。内质网（ER）应激是一种重要的适应性反应，可以在应激情况下维持细胞稳态。蛋白激酶R样内质网激酶（protein kinase R-like endoplasmic reticulum kinase，PERK）通路是内质网应激时激活最快的级联反应，对肝脏脂质代谢和自噬调控有重要影响。然而，在NEB条件下，NEFA是否可以通过调节PERK通路影响自噬尚不清楚。在这项研究中，我们提供的证据表明，NEFA处理显着增加脂质积累，PERK和真核起始因子2α（eIF 2 α）的磷酸化水平，以及葡萄糖调节蛋白78（Grp 78），转录激活因子4（ATF 4）和C/EBP同源蛋白（CHOP）的表达。更重要的是，NEFA治疗可导致自噬相关基因7（ATG 7）、Beclin-1（BECN 1）、多价螯合体-1（p62）和微管相关蛋白1轻链3（LC 3）-II的蛋白水平以及原代牛肝细胞中自噬体数量的显著增加。添加GSK 2656157（PERK磷酸化抑制剂）可以显著抑制NEFA对自噬的作用，并且可以进一步增加脂质积累。总之，我们的研究结果表明，NEFA可以促进自噬通过PERK途径在牛肝细胞。这些发现提供了新的证据PERK信号通路在维持牛肝细胞内稳态的潜在作用。
Negative energy balance can lead to the mobilization of large amounts of body fat. A large amount of non-esterified fatty acids (NEFA) produced by lipolysis not only can be used for energy generation by β-oxidation in the liver but can also act as a potential regulator of lipid metabolism. The present study provides evidence that NEFA can activate hepatocyte autophagy through the protein kinase R-like endoplasmic reticulum kinase (PERK) signaling pathway. Autophagy has been reported to contribute to lipid metabolism through promoting the breakdown of intracellular lipids. These findings enable a better understanding of the redistribution and utilization of energy during the perinatal period of dairy cows. During the perinatal period, the abnormally high plasma non-esterified fatty acids (NEFA) concentration caused by the negative energy balance (NEB) can impose a significant metabolic stress on the liver of dairy cows. Endoplasmic reticulum (ER) stress is an important adaptive response that can serve to maintain cell homeostasis in the event of stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is the most rapidly activated cascade when ER stress occurs in cells and has an important impact on the regulation of hepatic lipid metabolism and autophagy modulation. However, it is unknown whether NEFA can affect autophagy through modulating the PERK pathway, under NEB conditions. In this study, we provide evidence that NEFA treatment markedly increased lipid accumulation, the phosphorylation level of PERK and eukaryotic initiation factor 2α (eIF2α), and the expression of glucose-regulated protein 78 (Grp78), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). More importantly, NEFA treatment can cause a substantial increase in the protein levels of autophagy-related gene 7 (ATG7), Beclin-1 (BECN1), sequestosome-1 (p62), and microtubule-associated protein 1 light chain 3 (LC3)-II, and in the number of autophagosomes in primary bovine hepatocytes. The addition of GSK2656157 (PERK phosphorylation inhibitor) can significantly inhibit the effect of NEFA on autophagy and can further increase lipid accumulation. Overall, our results indicate that NEFA could promote autophagy via the PERK pathway in bovine hepatocytes. These findings provide novel evidence about the potential role of the PERK signaling pathway in maintaining bovine hepatocyte homeostasis.
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DOI：
10.1038/nrgastro.2013.211
发表时间：
2014-03
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lee, Jae Man;Wagner, Martin;Xiao, Rui;Kim, Kang Ho;Feng, Dan;Lazar, Mitchell A.;Moore, David D.
通讯作者：
Moore, David D.
影响因子：
7.1
作者：
Garcia-Esparcia P;Hernández-Ortega K;Koneti A;Gil L;Delgado-Morales R;Castaño E;Carmona M;Ferrer I
通讯作者：
Ferrer I
影响因子：
16
作者：
Ganley IG;Wong PM;Gammoh N;Jiang X
通讯作者：
Jiang X
影响因子：
8
作者：
Rzymski, T.;Milani, M.;Harris, A. L.
通讯作者：
Harris, A. L.