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Familial hypercholesterolemia: the lipids or the genes?

Fahed AC, Nemer GM - Nutr Metab (Lond) (2011)

Bottom Line: Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved.After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect.We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, American University of Beirut, Bliss Street, Beirut, P,O, Box 11-0236, Lebanon. gn08@aub.edu.lb.

ABSTRACT
Familial Hypercholesterolemia (FH) is a common cause of premature cardiovascular disease and is often undiagnosed in young people. Although the disease is diagnosed clinically by high LDL cholesterol levels and family history, to date there are no single internationally accepted criteria for the diagnosis of FH. Several genes have been shown to be involved in FH; yet determining the implications of the different mutations on the phenotype remains a hard task. The polygenetic nature of FH is being enhanced by the discovery of new genes that serve as modifiers. Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved. Because of this evolving polygenetic nature, the diagnosis of FH by genetic testing is hampered by its cost and effectiveness.In this review, we reconsider the clinical versus genetic nomenclature of FH in the literature. After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect. We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

No MeSH data available.


Related in: MedlinePlus

Molecular Pathways of Disease in Familial Hypercholesterolemia (1) The LDL receptor on the surface of hepatocytes binds ApoB-100 of the LDL particle forming a complex. (2) A clathrin-coated pit is formed and the ligand-receptor complex is endocytosed via interactions involving the LDLR Adaptor Protein 1 (LDLRAP1). (3) Inside the hepatocyte, the complex dissociates, the LDLR recycles to the cell membrane, (4) and free cholesterol is used inside the cell. (5) PCSK9 serves as a post-transcriptional inhibitor of LDLR. It is secreted and inhibits LDLR through cell-surface interactions. (6) The presence of an intracellular pathway for PCSK9-mediated LDLR inhibition is still a subject of controversy. (7) In response to decreased cholesterol such as during treatment with statins, Steroid Response Element Binding Protein (SREBP) binds to the Steroid Response Element (SRE) on the DNA and induces the transcription of the LDLR. (8) The sterol-responsive nuclear receptor LXR on the other hand responds to increased intracellular cholesterol inducing the transcription of IDOL, a recently discovered molecule that induces the ubiquitin-mediated degradation of the LDLR. Clouds in the figure refer to genes in which mutations have been associated with increased LDL-C levels.
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Figure 1: Molecular Pathways of Disease in Familial Hypercholesterolemia (1) The LDL receptor on the surface of hepatocytes binds ApoB-100 of the LDL particle forming a complex. (2) A clathrin-coated pit is formed and the ligand-receptor complex is endocytosed via interactions involving the LDLR Adaptor Protein 1 (LDLRAP1). (3) Inside the hepatocyte, the complex dissociates, the LDLR recycles to the cell membrane, (4) and free cholesterol is used inside the cell. (5) PCSK9 serves as a post-transcriptional inhibitor of LDLR. It is secreted and inhibits LDLR through cell-surface interactions. (6) The presence of an intracellular pathway for PCSK9-mediated LDLR inhibition is still a subject of controversy. (7) In response to decreased cholesterol such as during treatment with statins, Steroid Response Element Binding Protein (SREBP) binds to the Steroid Response Element (SRE) on the DNA and induces the transcription of the LDLR. (8) The sterol-responsive nuclear receptor LXR on the other hand responds to increased intracellular cholesterol inducing the transcription of IDOL, a recently discovered molecule that induces the ubiquitin-mediated degradation of the LDLR. Clouds in the figure refer to genes in which mutations have been associated with increased LDL-C levels.

Mentions: The pathway was first described by Brown and Goldstein in 1986 [4]. LDL in the blood has Apolipoprotein B-100 (ApoB-100) on its surface. The LDL receptor (LDLR) is a glycoprotein found on the surface of hepatocytes and binds ApoB-100 of the LDL-C. A clathrin-coated pit is formed and both receptor and LDL-C ligand are taken into an endosome with other proteins via interactions involving the LDLR adaptor protein 1 (LDLRAP1). After dissociation of the ligand-receptor complex, LDLR is recycled to the cell membrane, while free cholesterol is used inside the cell. PCSK9 serves as a post-transcriptional LDLR inhibitor. It is secreted outside the cell and inhibits LDLR through cell surface interactions. Evidence also suggests an intracellular pathway of PCSK9-mediated LDLR inhibition, however the exact mechanism is yet to be elucidated [11]. Nuclear regulation of LDLR production includes two pathways. First, the binding of a Steroid Response Element Binding Protein (SREBP) to a Steroid Response Element (SRE) on the DNA stimulates the transcription of the LDLR in response to decreased intracellular cholesterol [11]. This pathway is activated during treatment with HMG-CoA Reductase inhibitors. The second player in LDLR regulation is another sterol-mediated nuclear receptor LXR, which was recently shown to induce the transcription of IDOL (Inducible Degrader of the LDLR). As its name implies, IDOL triggers ubiquitinization of the LDLR targeting it for degradation [12]. (Figure 1) This pathway ensures proper uptake of LDL-C from the blood. Any defect in this pathway results in improper uptake and high LDL-C in the blood leading to the clinical manifestations of FH.


Familial hypercholesterolemia: the lipids or the genes?

Fahed AC, Nemer GM - Nutr Metab (Lond) (2011)

Molecular Pathways of Disease in Familial Hypercholesterolemia (1) The LDL receptor on the surface of hepatocytes binds ApoB-100 of the LDL particle forming a complex. (2) A clathrin-coated pit is formed and the ligand-receptor complex is endocytosed via interactions involving the LDLR Adaptor Protein 1 (LDLRAP1). (3) Inside the hepatocyte, the complex dissociates, the LDLR recycles to the cell membrane, (4) and free cholesterol is used inside the cell. (5) PCSK9 serves as a post-transcriptional inhibitor of LDLR. It is secreted and inhibits LDLR through cell-surface interactions. (6) The presence of an intracellular pathway for PCSK9-mediated LDLR inhibition is still a subject of controversy. (7) In response to decreased cholesterol such as during treatment with statins, Steroid Response Element Binding Protein (SREBP) binds to the Steroid Response Element (SRE) on the DNA and induces the transcription of the LDLR. (8) The sterol-responsive nuclear receptor LXR on the other hand responds to increased intracellular cholesterol inducing the transcription of IDOL, a recently discovered molecule that induces the ubiquitin-mediated degradation of the LDLR. Clouds in the figure refer to genes in which mutations have been associated with increased LDL-C levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104361&req=5

Figure 1: Molecular Pathways of Disease in Familial Hypercholesterolemia (1) The LDL receptor on the surface of hepatocytes binds ApoB-100 of the LDL particle forming a complex. (2) A clathrin-coated pit is formed and the ligand-receptor complex is endocytosed via interactions involving the LDLR Adaptor Protein 1 (LDLRAP1). (3) Inside the hepatocyte, the complex dissociates, the LDLR recycles to the cell membrane, (4) and free cholesterol is used inside the cell. (5) PCSK9 serves as a post-transcriptional inhibitor of LDLR. It is secreted and inhibits LDLR through cell-surface interactions. (6) The presence of an intracellular pathway for PCSK9-mediated LDLR inhibition is still a subject of controversy. (7) In response to decreased cholesterol such as during treatment with statins, Steroid Response Element Binding Protein (SREBP) binds to the Steroid Response Element (SRE) on the DNA and induces the transcription of the LDLR. (8) The sterol-responsive nuclear receptor LXR on the other hand responds to increased intracellular cholesterol inducing the transcription of IDOL, a recently discovered molecule that induces the ubiquitin-mediated degradation of the LDLR. Clouds in the figure refer to genes in which mutations have been associated with increased LDL-C levels.
Mentions: The pathway was first described by Brown and Goldstein in 1986 [4]. LDL in the blood has Apolipoprotein B-100 (ApoB-100) on its surface. The LDL receptor (LDLR) is a glycoprotein found on the surface of hepatocytes and binds ApoB-100 of the LDL-C. A clathrin-coated pit is formed and both receptor and LDL-C ligand are taken into an endosome with other proteins via interactions involving the LDLR adaptor protein 1 (LDLRAP1). After dissociation of the ligand-receptor complex, LDLR is recycled to the cell membrane, while free cholesterol is used inside the cell. PCSK9 serves as a post-transcriptional LDLR inhibitor. It is secreted outside the cell and inhibits LDLR through cell surface interactions. Evidence also suggests an intracellular pathway of PCSK9-mediated LDLR inhibition, however the exact mechanism is yet to be elucidated [11]. Nuclear regulation of LDLR production includes two pathways. First, the binding of a Steroid Response Element Binding Protein (SREBP) to a Steroid Response Element (SRE) on the DNA stimulates the transcription of the LDLR in response to decreased intracellular cholesterol [11]. This pathway is activated during treatment with HMG-CoA Reductase inhibitors. The second player in LDLR regulation is another sterol-mediated nuclear receptor LXR, which was recently shown to induce the transcription of IDOL (Inducible Degrader of the LDLR). As its name implies, IDOL triggers ubiquitinization of the LDLR targeting it for degradation [12]. (Figure 1) This pathway ensures proper uptake of LDL-C from the blood. Any defect in this pathway results in improper uptake and high LDL-C in the blood leading to the clinical manifestations of FH.

Bottom Line: Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved.After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect.We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, American University of Beirut, Bliss Street, Beirut, P,O, Box 11-0236, Lebanon. gn08@aub.edu.lb.

ABSTRACT
Familial Hypercholesterolemia (FH) is a common cause of premature cardiovascular disease and is often undiagnosed in young people. Although the disease is diagnosed clinically by high LDL cholesterol levels and family history, to date there are no single internationally accepted criteria for the diagnosis of FH. Several genes have been shown to be involved in FH; yet determining the implications of the different mutations on the phenotype remains a hard task. The polygenetic nature of FH is being enhanced by the discovery of new genes that serve as modifiers. Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved. Because of this evolving polygenetic nature, the diagnosis of FH by genetic testing is hampered by its cost and effectiveness.In this review, we reconsider the clinical versus genetic nomenclature of FH in the literature. After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect. We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

No MeSH data available.


Related in: MedlinePlus