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.