Triglyceride accumulation in injured renal tubular cells: Alterations in both synthetic and catabolic pathways
Triglyceride accumulation in injured renal tubular cells: Alterations in both synthetic and catabolic pathways
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DOI：
10.1111/j.1523-1755.2005.00325.x
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发表时间：
2005-06-01
影响因子：
19.6
通讯作者：
Zager, RA
中科院分区：
文献类型：
--
作者：
Johnson, ACM;Stahl, A;Zager, RA
背景。甘油三酯可以在受损组织中积累，这一过程被认为是过量的、细胞毒性的游离脂肪酸进入无毒甘油三酯储存池的过程。然而，考虑到多种途径可能影响甘油三酯水平，这种观点可能过于简单化。这项研究为这个问题寻求了新的见解。培养的人近端小管[人肾-2 (HK-2)]细胞或体内肾脏受到损伤，已知会使甘油三酯水平增加3至4倍[HK-2细胞抗霉素a诱导的线粒体阻断：体内甘油诱导的横横肌溶解，内毒素血症]。六种逆转录聚合酶链反应（rt - pcr）用于监测小鼠/人肾脂肪酸转运蛋白（FATP2）或甘油三酯合成酶（酰基辅酶A：二酰基甘油酰基转移酶DGAT1和DGAT2）的mrna。Western blot检测脂肪酸合成酶（FAS）和FATP2。FAS。探讨了FATP2、线粒体呼吸和磷脂酶A2 （PLA(2)）对细胞甘油三酯积累的影响。最后，测定组织脂肪酶活性。抗霉素A上调HK-2细胞甘油三酯形成的多个决定因素，包括FATP2、FAS、DGAT1和DGAT2（蛋白和/或mrna）。然而，FAS-和fatp2抑制都不能消除抗霉素a诱导的甘油三酯负荷，这表明后者是多因素基础。PLA(2)活性增加了FFA和甘油三酯含量。横纹肌溶解和内毒素血症改变了多种甘油三酯稳态机制。然而，这些变化是模型依赖性的，与HK-2细胞中的变化并不密切相似。脂肪酶活性显著下降（甘油）或上升（内毒素血症）与不同形式的组织损伤。损伤诱导的甘油三酯积累源于甘油三酯合成和降解途径的多种疾病特异性变化。过量游离脂肪酸进入甘油三酯池的简单通量是对损伤后甘油三酯负荷状态的过于简单化的看法。
Background. Triglycerides can accumulate in injured tissues, a process thought to represent flux of excess, cytotoxic, free fatty acids into nontoxic triglyceride storage pools. However, this view may be overly simplistic, given that multiple pathways may impact triglyceride levels. This study sought new insights into this issue.Methods. Cultured human proximal tubule [human kidney-2 (HK-2)] cells or in vivo kidney were subjected to injuries known to increase triglyceride levels similar to three- to fourfold [HK-2 cells antimycin A-induced mitochondrial blockade: in vivo glycerol-induced rhabdomyolysis, endotoxemia). Six reverse transcription-polymerase chain reactions (RT-PCRs) were used to monitor mouse/human mRNAs for renal fatty acid transport protein (FATP2), or triglyceride-synthesizing enzymes (acyl-coenzyme A:diacylglycerol acyltransferases DGAT1 and DGAT2). Fatty acid synthase (FAS) and FATP2 were gauged by Western blot. FAS. FATP2, mitochondrial respiration, and phospholipase A2 (PLA(2)) effects on cell triglyceride accumulation were probed. Finally, tissue lipase activity was assessed.Results. Antimycin A up-regulated multiple determinants of HK-2 cell triglyceride formation, including FATP2, FAS, DGAT1, and DGAT2 (proteins and/or mRNAs). However, neither FAS- nor FATP2-inhibition eliminated antimycin A-induced triglyceride loading, indicating the latter's multifactorial basis. PLA(2) activity increased FFA and triglyceride content. Rhabdomyolysis and endotoxemia altered multiple triglyceride homeostatic mechanisms. However, these changes were model-dependent and did not closely parallel those in HK-2 cells. Lipase activity signficantly fell (glycerol) or rose (endotoxemia) with different forms of tissue damage.Conclusion. Injury-induced triglyceride accumulation stems from multiple, and disease-specific, changes in triglyceride synthetic and degradative pathways. Simple flux of excess FFAs into triglyceride pools is an overly simplistic view of the post-injury-triglyceride loading state.