摘要
脂肪酸代谢主要包括脂肪酸氧化(fatty acid oxidation, FAO)和脂肪酸合成,其在信号转导、能量产生及炎症调节等过程均发挥重要作用。急性肾损伤(acute kidney injury, AKI)、慢性肾病(chronic kidney disease, CKD)与肾癌(renal cell carcinoma, RCC)是典型的肾脏疾病,发病机制复杂、易诱发多种并发症且临床尚无特异性干预措施。现有研究揭示,脂肪酸代谢与多种肾脏疾病的发生发展密切相关。文章综述了肾脏中脂肪酸的代谢特征、脂肪酸代谢失调与AKI、CKD及RCC等肾脏疾病的内在关系,总结了靶向脂肪酸代谢通路缓解肾脏疾病的中药及相关活性成分,为深入研究肾脏疾病脂肪酸代谢相关机制、寻找靶向干预手段提供理论参考。
据统计,全球大约有8.5亿人患有不同类型的肾脏疾
正常肾小管上皮细胞具有丰富的线粒体供应和旺盛的代谢活性,优先通过消耗脂肪酸供
脂肪酸氧化(fatty acid oxidation, FAO)主要发生在线粒体或过氧化物酶体,主要包括3个阶段:脂肪酸酯化、脂酰辅酶A(coenzyme A, CoA)的转移和脂酰CoA的β氧化。首先,脂肪酸在胞液中被CoA酯化成水溶性较强的脂酰CoA,长链脂酰CoA在肉碱棕榈酰转移酶系统介导下转运至线粒体基质,发生β氧化产生大量乙酰CoA。乙酰CoA一方面进入三羧酸循环氧化供能,另一方面为酮体和类固醇等化合物的合成提供原
脂肪酸合成的直接原料是乙酰CoA,它来源于糖、酮体和蛋白质等的分解代谢。乙酰CoA不易透过线粒体外膜,需通过柠檬酸-丙酮酸循环将乙酰CoA转运至胞液中。随后,乙酰CoA被乙酰CoA羧化酶(acetyl-CoA carboxylase, ACC)转化为丙二酰CoA,新生的脂肪酸链被脂肪酸合成酶(fatty acid synthase, FASN)不断延长,直至合成诸如棕榈酸等产物。在此过程中,ACC和FASN受到固醇调节元件结合蛋白(sterol-regulatory element binding protein, SREBP)的直接调控,而SREBP是一种公认的介导肾脏脂毒性、促进肾脏疾病发展的转录因
脂肪酸摄取、氧化和合成失衡与多种肾脏疾病进展密切相
疾病 | 临床诊断标准 | 数据来源 | 脂肪酸及相关代谢物 变化趋势 | 机制或通路 | 参考文献 |
---|---|---|---|---|---|
急性肾损伤 | 7 d内血清肌酐和尿素氮的迅速升高,伴随排尿量骤减(血清肌酐升高至基线值的1.5倍及以上;尿量<0.5 mL/(kg·h),持续6 h) | 急性肾损伤患者 | 短/中链酰基肉碱↑ | FAO↓ |
[ |
缺血再灌注急性肾损伤大鼠 |
长链饱和脂肪酸↑ 单不饱和脂肪酸↑ | 脂肪酸生物合成↑ |
[ | ||
缺血再灌注急性肾损伤小鼠 |
单/多不饱和脂肪酸↑ 中/长链饱和酰基肉碱↓ 多不饱和酰基肉碱↓ |
CPT1A↓ MCAD↓ |
[ | ||
顺铂急性肾损伤小鼠 | 短链酰基肉碱↑ | FAO↓ |
[ | ||
顺铂急性肾损伤大鼠 |
长链饱和酰基肉碱↑ 单/多不饱和酰基肉碱↑ |
FAO↓ 酰基肉碱排泄↓ |
[ | ||
慢性肾病 |
肾脏结构或功能的持续异常(如体表面积每1.73 | 慢性肾病患者 | 长链饱和脂肪酸↑ | FAO↓ |
[ |
慢性肾病患者 |
长链饱和脂肪酸↑ 多不饱和脂肪酸↓ | FAO调节因子↓ |
[ | ||
糖尿病肾病小鼠 |
长链饱和脂肪酸↑ 单不饱和脂肪酸↓ 多不饱和脂肪酸↑ |
CPT1A↓ FASN↑ |
[ | ||
肾癌 | 透明细胞癌(60% ~ 70%):PAX8染色阳性;乳头状细胞癌(10% ~ 20%):AE1/3、CAM5.2染色阳性;嫌色细胞癌(5% ~ 7%):CD117、小白蛋白和肾脏特异性钙黏蛋白染色阳性 | 透明细胞癌患者 |
短/中链脂肪酸↓ 长链脂肪酸↑ | FAO↓ |
[ |
透明细胞癌患者 |
长链饱和脂肪酸↑ 多不饱和脂肪酸↑ |
CPT1A↓ FAO↓ |
[ | ||
透明细胞癌患者 | 肉碱/短/长链酰基肉碱↑ | 脂肪酸代谢失调 |
[ | ||
透明细胞癌患者 |
长链饱和脂肪酸↑ 单不饱和脂肪酸↑ | 脂肪酸合成↑ |
[ | ||
肾癌转基因小鼠 | 单/多不饱和脂肪酸↑ | 脂质生物合成↑ |
[ |
↑表示上调或增强,↓表示下调或减弱
AKI是由败血症、缺血再灌注、肾毒性药物等引起的7 d内血清肌酐和尿素氮的迅速升高,伴随排尿量骤减的一种临床综合征。据统计,住院患者中AKI的发病率高达20
已有代谢组学研究表明,多种诱因引起的AKI均伴随脂肪酸代谢紊乱,如一项基于34例AKI患者的血清代谢组学研究发现,乙酰肉碱和3种中链酰基肉碱(辛酰肉碱、癸烯酰肉碱及癸酰肉碱)水平在AKI患者血清中显著升
AKI中脂肪酸代谢紊乱提示调控通路中的相关代谢酶可能发挥潜在疾病干预作用(

图1 急性肾损伤(AKI)中的脂肪酸代谢失调
CD36:脂肪酸转位酶;CPT1A:肉碱棕榈酰转移酶1A;CypD:线粒体亲环蛋白D;FABP4:脂肪酸结合蛋白4;FAO genes:脂肪酸氧化基因;Fibrates:贝特类;PPARα:过氧化物酶体增殖物激活受体α
临床上CKD定义为肾脏结构或功能的持续异常(如体表面积每1.73
CKD患者的脂肪酸代谢紊乱主要表现为(

图2 慢性肾病(CKD)中的脂肪酸代谢失调
ACC:乙酰CoA羧化酶; Chiglitazar:西格列他钠;CPT1A:肉碱棕榈酰转移酶1A; FASN:脂肪酸合酶;MCP1:单核细胞趋化蛋白1;mtDNA:线粒体DNA;PGC1α:过氧化物酶体增殖物激活受体γ共激活因子1α; ROS:活性氧;SREBP:固醇调节元件结合蛋白;TGF-β1:转化生长因子β1
研究证实靶向调控PPARα及其下游代谢酶可有效缓解CKD。例如,在叶酸和单侧输尿管结扎诱导的肾纤维化模型中,PPARα激动剂非诺贝特通过恢复FAO相关代谢酶的表达改善肾损伤和纤维
据癌症中心的最新数据,2015年我国新发RCC为66.8万例,死亡人数为23.4万
在RCC的发展过程中,FAO途径被抑制而细胞内脂质储存大大增加(

图3 肾癌(RCC)中的脂肪酸代谢失调
SCD1:硬脂酰CoA去饱和酶;红色箭头表示上调或增强,蓝色箭头表示下调或减弱
脂肪酸合成方面,有研究发现RCC中脂质的储存可通过维持内质网稳态促进肿瘤细胞的存
脂肪酸代谢失调与肾脏疾病的发生发展密切相关,因此靶向调控肾脏脂肪酸代谢或可缓解肾脏损伤。此外,线粒体功能障碍所致的脂肪酸代谢紊乱亦是肾脏损伤的促进因素。长久以来,中药及其活性成分在预防和治疗各种疾病中发挥了关键作用,是新药研发、药品制备的重要来源,本文系统总结了回调脂肪酸代谢相关代谢物、调控脂肪酸代谢相关代谢酶以及改善线粒体功能障碍缓解各种肾脏疾病的相关研究(
中药类别 | 名称 | 肾脏疾病 | 调控因素 | 参考文献 |
---|---|---|---|---|
方剂/制剂 | 滋肾清热通络方 | 高尿酸血症肾病 | PGC-1α↑ |
[ |
PPARα↑ | ||||
FAO↑ | ||||
真武汤 | 肾纤维化 | 脂肪酸 |
[ | |
黄葵胶囊 | 糖尿病肾病 | 亚油酸 |
[ | |
药材 | 大黄 | 慢性肾衰 | 脂肪酸 |
[ |
茯苓皮 | 慢性肾病 | 脂肪酸 |
[ | |
活性成分 | 大黄酸 | 肾纤维化 | CPT1A↑ |
[ |
FAO↑ | ||||
三七皂苷 | 顺铂急性肾损伤 | 线粒体损伤↓ |
[ | |
黄芪甲苷Ⅳ | 顺铂急性肾损伤 | 脂肪酸 |
[ | |
山柰酚 | 顺铂急性肾损伤 | 酰基肉碱 |
[ | |
雷公藤红素 | 顺铂急性肾损伤 | 线粒体功能↑ |
[ | |
小檗碱 | 糖尿病肾病 | PGC-1α↑ |
[ | |
线粒体能量稳态↑ | ||||
骆驼蓬碱 | 肾纤维化 | PGC-1α↑ |
[ | |
PPARα↑ | ||||
CPT1A↑ | ||||
FAO↑ | ||||
三七多糖 | 糖尿病肾病 | SREBP↓ |
[ | |
ACC↓ 脂质蓄积↓ | ||||
花青素 | 糖尿病肾病 | AMPK↑ |
[ | |
SREBP↓ ACC↓ | ||||
脂质蓄积↓ |
真武汤由茯苓、芍药、生姜、附子、白术组成,是临床常用方剂,具有温阳利水、健脾燥湿的功效。Li
滋肾清热通络方是由《金匮要略》中的白虎桂芝汤改制而来,以知母、石膏、桂枝、甘草、薏苡仁、山药配比组成,已被用于治疗高尿酸血症肾病。体内研究表明,滋肾清热通络方可通过介导TGF-β1/Smad3信号通路,显著上调PGC-1α和PPARα蛋白表达,改善肾脏FAO发挥肾脏保护作
综上,本文以典型肾脏疾病AKI、CKD与RCC为代表,系统阐述了肾脏疾病与脂肪酸代谢的内在关系。值得注意的是,PPARα在多种肾脏疾病中均发挥着重要的调控作用,虽然PPARs全激动剂西格列他钠在我国获批上市且已有多个PPARα激动剂获得临床批件,但这些药物在肾脏疾病中的作用有待进一步验证。
此外,调节脂肪酸代谢的中药及其活性成分已应用于治疗各种肾病,部分中药已深入分子水平的实验研究和评价,但在应用方面仍基于临床经验,或局限于动物实验研究,尚缺乏临床试验依据。因此,在传承中医药理论基础上,开发出临床上安全有效、机制明确的中药制剂或组合,有望为肾脏疾病的治疗带来新突破。
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