Familial hyperlipidemia type 4 (WP5111)

Homo sapiens

Familial hyperlipidemias are classified according to the Fredrickson classification. Type IV familial hyperlipidemia is also known as familial hypertriglyceridemia. Typ IV is mostly linked to in increased VLDL within the blood. This is from both an increased production as well as a decreased elimination of VLDL. The increased production is caused by mutations of GCKR. This gene inhibits glucokinase, which would lead to less triglycerides produced in the liver. These triglycerides would then increase the amount of VLDL in the blood. Mutations in GCKR would therefore lead to increased VLDL. A decreased elimination is caused by APOA5. APOA5 plays a role in the hydrolysis of VDLD by LPL. Mutations in this gene would therefore lead to a decrease of this hydrolysis.

Authors

Ulas Babayigit , Egon Willighagen , and Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Disease Ontology

familial hyperlipidemia hyperlipoproteinemia type IV

Cell Type Ontology

hepatocyte

Pathway Ontology

disease pathway

Participants

Label Type Compact URI Comment
Malonyl-CoA Metabolite chebi:15531
VLDL Metabolite chebi:39027
Cholesterol Metabolite chebi:16113
HDL Metabolite chebi:47775
LDL Metabolite chebi:47774
Lipoprotein Metabolite chebi:6495
IDL Metabolite chebi:132933
Fatty acid Metabolite chebi:35366
Acyl-CoA Metabolite chebi:15522
Triglyceride Metabolite chebi:17855
Phospholipid Metabolite chebi:16247
DGAT2 GeneProduct ensembl:ENSG00000062282
GCKR GeneProduct ensembl:ENSG00000084734
FAS GeneProduct ensembl:ENSG00000026103
SEL1L GeneProduct ensembl:ENSG00000071537
APOA2 GeneProduct ensembl:ENSG00000158874
LRP1 GeneProduct ensembl:ENSG00000123384
APOA4 GeneProduct ensembl:ENSG00000110244
CETP GeneProduct ensembl:ENSG00000087237
LIPC GeneProduct ensembl:ENSG00000166035
APOA1 GeneProduct ensembl:ENSG00000118137
LCAT GeneProduct ensembl:ENSG00000213398
LDLR GeneProduct ensembl:ENSG00000130164
PLTP GeneProduct ensembl:ENSG00000100979
LPL GeneProduct ensembl:ENSG00000175445
LMF1 GeneProduct ensembl:ENSG00000103227
GPIHBP1 GeneProduct ensembl:ENSG00000277494
APOC2 GeneProduct ensembl:ENSG00000234906
APOA5 GeneProduct ensembl:ENSG00000110243
PDIA2 GeneProduct ensembl:ENSG00000185615
MTTP GeneProduct ensembl:ENSG00000138823
Glucokinase Protein uniprot:P35557
Acyl-CoA synthetase Protein ensembl:ENSG00000154930

References

  1. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Johansen CT, Wang J, Lanktree MB, Cao H, McIntyre AD, Ban MR, et al. Nat Genet. 2010 Aug;42(8):684–7. PubMed Europe PMC Scholia
  2. Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. Jeong YS, Kim D, Lee YS, Kim HJ, Han JY, Im SS, et al. PLoS One. 2011;6(7):e22544. PubMed Europe PMC Scholia
  3. Unraveling the genetics of fatty liver in obese children: additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Valenti L, Alisi A, Nobili V. Hepatology. 2012 Mar;55(3):661–3. PubMed Europe PMC Scholia
  4. Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Go GW, Mani A. Yale J Biol Med. 2012 Mar;85(1):19–28. PubMed Europe PMC Scholia
  5. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib. Goldberg AS, Hegele RA. Drug Des Devel Ther. 2012;6:251–9. PubMed Europe PMC Scholia
  6. Association of CETP and LIPC Gene Polymorphisms with HDL and LDL Sub-fraction Levels in a Group of Indian Subjects: A Cross-Sectional Study. Todur SP, Ashavaid TF. Indian J Clin Biochem. 2013 Apr;28(2):116–23. PubMed Europe PMC Scholia
  7. Introduction to Lipids and Lipoproteins. Feingold KR. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2021. PubMed Europe PMC Scholia
  8. Hypertriglyceridemia: Pathophysiology, Role of Genetics, Consequences, and Treatment. Chait A, Subramanian S. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2019. PubMed Europe PMC Scholia
  9. High-density lipoprotein metabolism and reverse cholesterol transport: strategies for raising HDL cholesterol. Tosheska Trajkovska K, Topuzovska S. Anatol J Cardiol. 2017 Aug;18(2):149–54. PubMed Europe PMC Scholia
  10. Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism. Wolska A, Dunbar RL, Freeman LA, Ueda M, Amar MJ, Sviridov DO, et al. Atherosclerosis. 2017 Dec;267:49–60. PubMed Europe PMC Scholia
  11. N-terminal mutation of apoA-I and interaction with ABCA1 reveal mechanisms of nascent HDL biogenesis. Liu M, Mei X, Herscovitz H, Atkinson D. J Lipid Res. 2019 Jan;60(1):44–57. PubMed Europe PMC Scholia
  12. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. Geller AS, Polisecki EY, Diffenderfer MR, Asztalos BF, Karathanasis SK, Hegele RA, et al. J Lipid Res. 2018 Dec;59(12):2421–35. PubMed Europe PMC Scholia
  13. Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice. Obinata H, Kuo A, Wada Y, Swendeman S, Liu CH, Blaho VA, et al. J Lipid Res. 2019 Nov;60(11):1912–21. PubMed Europe PMC Scholia
  14. Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis. Lucero D, Islam P, Freeman LA, Jin X, Pryor M, Tang J, et al. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb;1865(2):158537. PubMed Europe PMC Scholia
  15. Association between the APOA2 rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI. Boughanem H, Bandera-Merchán B, Hernández-Alonso P, Moreno-Morales N, Tinahones FJ, Lozano J, et al. Biomedicines. 2020 Feb 27;8(3):44. PubMed Europe PMC Scholia
  16. Lomitapide-a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia. Stefanutti C. Curr Atheroscler Rep. 2020 Jun 18;22(8):38. PubMed Europe PMC Scholia