title: Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome.
abstract: BACKGROUND
  Nephrotic syndrome (NS) leads to elevation of serum total and LDL cholesterol. This is largely due to impaired LDL clearance, which is caused by hepatic LDL receptor (LDLR) deficiency despite normal LDLR mRNA expression, pointing to a post-transcriptional process. The mechanism(s) by which NS causes LDLR deficiency is not known. By promoting degradation of LDLR, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and inducible degrader of the LDL receptor (IDOL) play a major role in post-translational regulation of LDLR. We, therefore, tested the hypothesis that LDLR deficiency despite its normal gene expression in NS may be due to upregulation of hepatic PCSK9 and IDOL.
  
  
  METHODS
  LDLR, IDOL and PCSK9 expressions and nuclear translocation of liver X receptor (LXR) that regulates IDOL expression were determined in the liver of rats with puromycin-induced NS and control (CTL) rats.
  
  
  RESULTS
  Compared with the CTLs, the NS rats showed marked elevation of serum total and LDL cholesterol and a significant reduction in hepatic LDLR protein expression. This was accompanied by marked upregulation of hepatic PCSK9 and IDOL expressions and heightened LXR activation.
  
  
  CONCLUSIONS
  LDLR deficiency, hypercholesterolemia and elevated plasma LDL in NS are associated with upregulation of PCSK9 and IDOL. Interventions targeting these pathways may be effective in the management of hypercholesterolemia and the associated cardiovascular and other complications of NS.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, CA, USA.
authors.forename: Shuman
authors.initials: S
authors.lastname: Liu
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D015870:Gene Expression; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D000071518:Liver X Receptors; D008297:Male; D009404:Nephrotic Syndrome / Q000097:blood / Q000201:enzymology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D000071449:Proprotein Convertase 9; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL; D012697:Serine Endopeptidases / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D008078:Cholesterol, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C584833:Mylip protein, rat; D044767:Ubiquitin-Protein Ligases; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases
keywords: atherosclerosis; lipid disorders; liver X receptor; proteinuria