Hepatic tissue sterol regulatory element binding protein 2 and low-density lipoprotein receptor in nephrotic syndrome.
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.
Kim
Choong H
CH
Division of Nephrology and Hypertension, University of California, Irvine, Orange, CA 92868, USA.
Kim
Hyun J
HJ
Mitsuhashi
Masato
M
Vaziri
Nosratola D
ND
D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers; D003627:Data Interpretation, Statistical; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*
D017931:DNA Primers; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C470194:Srebf2 protein, rat; D051779:Sterol Regulatory Element Binding Proteins; D006903:Hydroxymethylglutaryl CoA Reductases