title: Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia.
abstract: OBJECTIVE
  Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL.
  
  
  RESULTS
  Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001).
  
  
  CONCLUSIONS
  The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.
authors: Department of Internal Medicine, divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: Martijn.brouwers@maastrichtuniversity.nl.
authors: M C G J
authors: MC
authors: Brouwers
authors: R J
authors: RJ
authors: Konrad
authors: T M
authors: TM
authors: van Himbergen
authors: A
authors: A
authors: Isaacs
authors: S
authors: S
authors: Otokozawa
authors: J S
authors: JS
authors: Troutt
authors: E J
authors: EJ
authors: Schaefer
authors: M M J
authors: MM
authors: van Greevenbroek
authors: A F H
authors: AF
authors: Stalenhoef
authors: J
authors: J
authors: de Graaf
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D015331:Cohort Studies; D003897:Desmosterol / Q000097:blood; D005190:Family; D005260:Female; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D009426:Netherlands; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D012044:Regression Analysis; D015203:Reproducibility of Results; D012697:Serine Endopeptidases / Q000097:blood*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D003897:Desmosterol; C001521:lathosterol; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: BMI; CAD; Cholesterol; FCHL; HDL cholesterol; HDL-C; LDL; LDL cholesterol; LDL receptor; LDL-C; LDLR; Lipid metabolism; PCSK9; RLPC; SOLAR; SPSS; SREBP2; Sequential Oligogenic Linkage Analysis Routines; Statistical Package of Social Sciences; VLDL cholesterol; VLDL triglycerides; VLDL-C; VLDL-TG; body mass index; coronary artery disease; familial combined hyperlipidemia; proprotein convertase subtilisin kexin type 9; remnant lipoprotein cholesterol; sdLDL-C; small-dense LDL cholesterol; sterol regulatory element binding protein 2