通过抑制 HNF4α 介导的 FGF21 敏感性,p53 的升高使肥胖肾脏对阿霉素诱导的异常脂质稳态敏感。

Jiahao Li, Yufeng Tang, Guangping Lu, Qingbo Liu, Yuanfang Guo, Jie Wang, Mengjie Xiao, Ting Gao, Xiaohui Zhang, Junlian Gu
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引用次数: 0

摘要

简介脂质代谢紊乱已被证实分别与阿霉素(ADR)和肥胖引起的肾损伤密切相关。然而,脂质代谢紊乱是否与肥胖加重的 ADR 引起的肾损伤有关尚未探明,具体的分子机制也有待进一步阐明:本研究旨在探讨p53-成纤维细胞生长因子21(FGF21)轴在高脂饮食(HFD)加重ADR诱导的肾损伤中的作用:方法:我们设计了Fgf21 KO小鼠,并使用长期(4个月)和短期(0.5个月)HFD喂养、ADR注射小鼠以及STZ诱导的1型糖尿病小鼠和2型(db/db)糖尿病小鼠来制作体内肾毒性模型。随后,综合运用功能和病理分析、RNA测序、分子生物学和体外方法,阐明了p53/FGF21对肾脏脂质代谢紊乱及其下游介质调节的具体影响:结果:长期摄入高氟日粮的小鼠在服用 ADR 后,FGF21 对缓解肾功能障碍和脂质积累的作用受到影响。然而,p53 抑制剂(pifithrin-α,PFT-α)可逆转这些损伤。PFT-α 使 FGF21 在肾组织中的作用变得敏感,而 Fgf21 基因敲除则削弱了 PFT-α 对脂质代谢的保护作用。从机理上讲,p53通过抑制肝细胞核因子α(HNF4α)介导的Fgfr1转录激活,损害了肾脏中FGF受体-1(FGFR1)的表达,从而逐渐发展成FGF21抗性。更重要的是,外源性补充FGF21或PFT-α不仅能缓解高脂饮食导致的ADR诱导的脂质代谢紊乱,还能减少糖尿病肾病引起的脂质蓄积:结论:鉴于开发长效重组FGF21类似物用于治疗存在困难,通过抑制p53使肥胖受损的FGF21作用敏感化可能是化疗期间维持肾脏代谢平衡的一种治疗策略。
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Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity.

Introduction: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified.

Objectives: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD).

Methods: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches.

Results: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy.

Conclusion: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.

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