Hepatic tissue sterol regulatory element binding protein 2 and low-density lipoprotein receptor in nephrotic syndrome
Hepatic tissue sterol regulatory element binding protein 2 and low-density lipoprotein receptor in nephrotic syndrome
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DOI：
10.1016/j.metabol.2007.05.007
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发表时间：
2007-10-01
影响因子：
9.8
通讯作者：
Vaziri, Nosratola D.
中科院分区：
文献类型：
--
作者：
Kim, Choong H.;Kim, Hyun J.;Vaziri, Nosratola D.
高胆固醇血症是肾病综合征（NS）的主要特征，部分是由获得性低密度脂蛋白（LDL）受体缺乏引起的。NS中的LDL受体缺乏伴随着正常的肝LDL受体信使RNA（mRNA）丰度。LDL受体、3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶和其他几种胆固醇调节因子的表达受固醇调节元件结合蛋白2（SREBP-2）调节。本研究验证了肾病高胆固醇血症可能与肝组织SREBP-2丰度或活性失调相关的假设。SREBP-2，LDL受体，HMG-CoA还原酶的蛋白质和mRNA丰度在慢性嘌呤霉素诱导的NS大鼠和对照大鼠的肝脏中进行了测定。肾病组表现出重度蛋白尿、低白蛋白血症、严重高胆固醇血症，肝组织总胆固醇和游离胆固醇浓度正常。尽管有严重的高胆固醇血症，非活性微粒体和活性核SREBP-2水平在肾病动物的肝脏中没有变化。这与LDL受体蛋白丰度的显著降低有关。证实了我们早期的研究，LDL受体和HMG-CoA还原酶mRNA水平在肾病动物中没有变化。高胆固醇血症肾病大鼠的肝脏SREBP-2丰度和活性与正常胆固醇血症对照动物相似，代表适应不良反应。这种矛盾可能部分是由于获得性LDL受体缺陷，其有助于维持SREBP-2表达/活性并通过限制肝脏胆固醇摄取来维持高胆固醇血症。这是因为SREBP-2的表达和活性部分受细胞内而不是血浆胆固醇的调节。(c)2007爱思唯尔公司All rights reserved.
Hypercholesterolemia is a main feature of nephrotic syndrome (NS) and is, in part, caused by acquired low-density lipoprotein (LDL) receptor deficiency. The LDL receptor deficiency in NS is accompanied by normal hepatic LDL receptor messenger RNA (mRNA) abundance. Expression of LDL receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and several other cholesterol-regulatory factors is regulated by sterol regulatory element binding protein 2 (SREBP-2). This study tested the hypothesis that nephrotic hypercholesterolemia may be associated with dysregulation of hepatic tissue SREBP-2 abundance or activity. Protein and mRNA abundance of SREBP-2, LDL receptor, and HMG-CoA reductase was determined in the livers of rats with chronic puromycin-induced NS and of control rats. The nephrotic group showed heavy proteinuria, hypoalbuminemia, severe hypercholesterolemia, and normal liver tissue total and free cholesterol concentrations. Despite severe hypercholesterolemia, the inactive microsomal and the active nuclear SREBP-2 levels were unchanged in the liver of the nephrotic animals. This was associated with a marked reduction in LDL receptor protein abundance. In confirmation of our earlier studies, LDL receptor and HMG-CoA reductase mRNA levels were unchanged in nephrotic animals. Hepatic SREBP-2 abundance and activity in hypercholesterolemic nephrotic rats were similar to those found in the normocholesterolemic control animals, representing a maladaptive response. This paradox may be, in part, due to acquired LDL receptor deficiency that helps sustain SREBP-2 expression/activity and maintain hypercholesterolemia by limiting hepatic cholesterol uptake. This is because SREBP-2 expression and activity are, in part, regulated by intracellular as opposed to plasma cholesterol. (c) 2007 Elsevier Inc. All rights reserved.