title: Familial combined hyperlipidemia: from molecular insights to tailored therapy.
abstract: OBJECTIVE
  This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL).
  
  
  RESULTS
  A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment.
  
  
  CONCLUSIONS
  Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.
authors.affiliation: aDepartments of Internal Medicine and Endocrinology, Maastricht University Medical Centre bCARIM School for Cardiovascular Diseases/Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht cDivision of Vascular Medicine, Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.forename: Martijn C G J
authors.initials: MC
authors.lastname: Brouwers
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C586298:SLC25A40 protein, human; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases