Liang Kaihui, Vaziri Nosratola D
Division of Nephrology and Hypertension, University of California, Irvine, California, USA.
Kidney Int. 2003 Jul;64(1):192-8. doi: 10.1046/j.1523-1755.2003.00041.x.
Hereditary analbuminemia is associated with hypercholesterolemia, which has been shown to be primarily caused by increased extrahepatic production of cholesterol. Nagase rats with hereditary analbuminemia (NAR) have been used as a model to dissect the effect of primary hypoalbuminemia from that caused by proteinuria in nephrotic syndrome. The present study was undertaken to explore the effect of hereditary analbuminemia on protein expression of the key factors involved in cholesterol metabolism.
Hepatic tissue protein abundance of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase (a rate-limiting enzyme in cholesterol catabolism), low density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor (SRB-1), acyl-coA cholesterol acyltransferase-2 (ACAT-2), and plasma concentration of lecithin cholesterol acyltransferase (LCAT), as well as HMG-CoA reductase, ACAT, and LCAT activities were determined in fasting male NAR and Sprague-Dawley control rats.
The NAR group exhibited significant up-regulation of HMG-CoA reductase protein abundance but normal HMG-CoA reductase enzymatic activity. This was coupled with a significant up-regulation of cholesterol 7alpha-hydroxylase and a mild up-regulation of ACAT protein abundance and activity. However, hepatic LDL receptor and HDL receptor and plasma LCAT protein concentration and activity were normal in NAR.
Hypercholesterolemia in NAR is associated with elevated hepatic HMG-CoA reductase protein abundance, but normal HMG-CoA reductase activity. These findings point to post-translational regulation of this enzyme and favor an extrahepatic origin of hypercholesterolemia in NAR. The observed up-regulation of cholesterol 7alpha-hydroxylase represents a compensatory response to the associated hypercholesterolemia. Unlike nephrotic syndrome, which causes severe LDL receptor, HDL receptor, and LCAT deficiencies, hereditary analbuminemia does not affect these proteins.
遗传性无白蛋白血症与高胆固醇血症相关，已表明这主要是由肝外胆固醇生成增加所致。遗传性无白蛋白血症的长谷部大鼠（NAR）已被用作模型，以剖析原发性低白蛋白血症与肾病综合征蛋白尿所致低白蛋白血症的影响。本研究旨在探讨遗传性无白蛋白血症对胆固醇代谢关键因子蛋白表达的影响。
测定禁食雄性NAR大鼠和Sprague-Dawley对照大鼠肝脏组织中3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶、胆固醇7α-羟化酶（胆固醇分解代谢中的限速酶）、低密度脂蛋白（LDL）受体、高密度脂蛋白（HDL）受体（SRB-1）、酰基辅酶A胆固醇酰基转移酶-2（ACAT-2）的蛋白丰度以及卵磷脂胆固醇酰基转移酶（LCAT）的血浆浓度，以及HMG-CoA还原酶、ACAT和LCAT的活性。
NAR组HMG-CoA还原酶蛋白丰度显著上调，但HMG-CoA还原酶酶活性正常。这与胆固醇7α-羟化酶的显著上调以及ACAT蛋白丰度和活性的轻度上调相关。然而，NAR组肝脏LDL受体和HDL受体以及血浆LCAT蛋白浓度和活性正常。
NAR中的高胆固醇血症与肝脏HMG-CoA还原酶蛋白丰度升高相关，但HMG-CoA还原酶活性正常。这些发现表明该酶存在翻译后调控，并支持NAR中高胆固醇血症的肝外起源。观察到的胆固醇7α-羟化酶上调代表了对相关高胆固醇血症的代偿反应。与导致严重LDL受体、HDL受体和LCAT缺乏的肾病综合征不同，遗传性无白蛋白血症不影响这些蛋白。
