Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis.
Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis.
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FATP2 介导的肾小管脂质代谢重编程参与肾纤维化
DOI：
10.1038/s41419-020-03199-x
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发表时间：
2020-11-20
影响因子：
9
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Chen Y;Yan Q;Lv M;Song K;Dai Y;Huang Y;Zhang L;Zhang C;Gao H
慢性损伤后，肾小管上皮细胞（TEC）通过脂质代谢失调导致脂质蓄积和脂毒性，从而促进肾纤维化的发展。细胞内脂质代谢受脂肪酸（FAs）摄取、氧化、脂肪生成和脂解的严格控制。虽然脂肪酸氧化受损（FAO）在肾纤维化进展中起着至关重要的作用，但其他脂质代谢途径，特别是脂肪酸摄取，尚未在纤维化肾脏中进行研究。在这项研究中，我们的目的是探讨在肾纤维化的发病机制中的潜在的机械作用的脂肪酸转运蛋白。本研究中，无偏基因表达研究表明，脂肪酸转运蛋白2（FATP 2）是TEC中主要表达的脂肪酸转运蛋白之一，其表达与肾功能下降密切相关。用FATP 2抑制剂（FATP 2 i）脂质体治疗单侧输尿管梗阻（UUO）肾和TGF-β诱导的TEC恢复了FAO活性，并减轻了体内和体外的纤维化反应。此外，促纤维化细胞因子包括TGF-β、结缔组织生长因子（CTGF）、成纤维细胞生长因子（FGF）和血小板衍生生长因子亚基B（PDGFB）的表达在FATP 2 i处理的UUO肾脏中均降低。在机械上，FATP 2 i可以有效地减弱由TGF-β处理在培养的TEC中诱导的细胞凋亡和内质网（ER）应激。综上所述，这些发现揭示了FATP 2通过诱导脂质代谢重编程（包括TEC中的异常FA摄取和缺陷性FAO）来促进对肾间质纤维化的促纤维化反应。
Following a chronic insult, renal tubular epithelial cells (TECs) contribute to the development of kidney fibrosis through dysregulated lipid metabolism that lead to lipid accumulation and lipotoxicity. Intracellular lipid metabolism is tightly controlled by fatty acids (FAs) uptake, oxidation, lipogenesis, and lipolysis. Although it is widely accepted that impaired fatty acids oxidation (FAO) play a crucial role in renal fibrosis progression, other lipid metabolic pathways, especially FAs uptake, has not been investigated in fibrotic kidney. In this study, we aim to explore the potential mechanically role of FAs transporter in the pathogenesis of renal fibrosis. In the present study, the unbiased gene expression studies showed that fatty acid transporter 2 (FATP2) was one of the predominant expressed FAs transport in TECs and its expression was tightly associated with the decline of renal function. Treatment of unilateral ureteral obstruction (UUO) kidneys and TGF-β induced TECs with FATP2 inhibitor (FATP2i) lipofermata restored the FAO activities and alleviated fibrotic responses both in vivo and in vitro. Moreover, the expression of profibrotic cytokines including TGF-β, connective tissue growth factor (CTGF), fibroblast growth factor (FGF), and platelet-derived growth factor subunit B (PDGFB) were all decreased in FATP2i-treated UUO kidneys. Mechanically, FATP2i can effectively attenuate cell apoptosis and endoplasmic reticulum (ER) stress induced by TGF-β treatment in cultured TECs. Taking together, these findings reveal that FATP2 elicits a profibrotic response to renal interstitial fibrosis by inducing lipid metabolic reprogramming including abnormal FAs uptake and defective FAO in TECs.
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DOI：
10.1042/bcj20160943
发表时间：
2017-04-24
期刊：
The Biochemical journal
影响因子：
--
作者：
Lakshmi SP;Reddy AT;Reddy RC
通讯作者：
Reddy RC
影响因子：
13.6
作者：
Burns, Wendy C.;Twigg, Stephen M.;Kantharidis, Phillip
通讯作者：
Kantharidis, Phillip
影响因子：
4.8
作者：
Martin, G;Schoonjans, K;Auwerx, J
通讯作者：
Auwerx, J
影响因子：
15.9
作者：
Gomez, Ivan G.;MacKenna, Deidre A.;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.
影响因子：
64.5
作者：
Hotamisligil GS
通讯作者：
Hotamisligil GS