Lipid Metabolism in Familial Hypercholesterolemia

Size: px

Start display at page:

Download "Lipid Metabolism in Familial Hypercholesterolemia"

Willa Melissa Fisher
5 years ago
Views:

1 Lipid Metabolism in Familial Hypercholesterolemia Khalid Al-Rasadi, BSc, MD, FRCPC Head of Biochemistry Department, SQU Head of Lipid and LDL-Apheresis Unit, SQUH President of Oman society of Lipid & Atherosclerosis (OSLA)

2 Disclosures Honoraria for Speakers Bureau (Pharma) AstraZeneca, Sanofi, Pfizer Advisory Boards: Sanofi, Aegerion, AstraZeneca Research Funding: Pfizer

3 Cholesterol Importance A stabilizing component of cell membranes A precursor of bile salts A precursor of steroid hormones A cholesterol precursor is converted to cholecalciferol (vit. D)

Normal absorption: 50% For cholesterol to be absorbed it must: undergo hydrolysis (de-esterification by

5 NORMAL CHOLESTEROL METABOLISM Synthesis Primary synthetic sites are extrahepatic, but liver is key regulator of homeostasis Absorption Largest source is biliary secretion, not diet. Normal absorption: 50% For cholesterol to be absorbed it must: undergo hydrolysis (de-esterification by esterases) be incorporated into micelles be taken up by cholesterol transporter be re-esterified and incorporated into chylomicrons

6 NORMAL CHOLESTEROL ABSORPTION 400 mg/day 1,300 mg/day Oil phase 17,400 mg/day 850 mg/day

7 HMG CoA Reductase (More Than Cholesterol Synthesis) Acetyl CoA Prenylation of signalling peptides (ras, rho, etc.) HMG CoA Reductase Dolichols HMG CoA Mevalonate Farnesyl Pyrophosphate Cholesterol Isopentenyl adenine (transfer RNA) Ubiquinones (CoQ-10, etc.) Inhibition of other key products of mevalonate may relate to nonlipid effects & rare side effects of statins.

8 Lipoprotein Metabolism and Atherosclerosis LDL clearance Lambert et al. J. Lipid Res :

Receptor-Mediated Endocytosis of Lipoproteins LDL receptor are located at coated pits, which also contain clathrin Vesicles fuse with lysosome where

9 Receptor-Mediated Endocytosis of Lipoproteins LDL receptor are located at coated pits, which also contain clathrin Vesicles fuse with lysosome where cholesterol esters are hydrolyzed into cholesterol & re-esterified by ACAT This avoids damaging effects of high concentrations of free cholesterol on membrane

10 LDL Receptor (apob-e receptor) Regulates cholesterol synthesis and plasma cholesterol levels LDL-Receptors LDL Receptors HMG-CoA reductase SREBP Cholesteryl ester (storage) ACAT LDL LDL Endosome Lysosome Cholesterol Amino acids

11 PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) the 9th member of the proprotein convertase family of proteins that activate other proteins involved in the degradation of low-density lipoprotein (LDL) receptors in the liver.

12 The LDLR Pathway

13 Lipoproteins Function: Lipid transport (cholesterol, cholesterol esters, triacylglycerols, phospholipids) Structure: A nucleus: triacylglycerols, cholesterol esters A shell: phospholipids, apoproteins, cholesterol

14 Composition of lipoproteins

15 Apolipoproteins Major function: structure, solubility, activation of enzyme, ligands for receptors Apoprotein Function Apo A-I activates LCAT, structural component of HDL Apo B-48 Assembly and secretion of chylomicrons Apo B-100 Apo C-II VLDL assembly and secretion; structural protein of VLDL, IDL and LDL; ligand for LDL receptor Activator of lipoprotein lipase (LPL) Apo E ligand to LDL receptor; ligand to Apo E receptor

16 Familial Hypercholesterolemia: Prevalence and Risk FH is caused by genetic mutations passed on by: One parent (heterozygous, HeFH) 1 Both parents (homozygous, HoFH) 1 HoFH prevalence ranges from 1 in 160,000 to 1 in 250,000 2,3 Individuals with HoFH have extremely high LDL-C levels (>500 mg/dl) and premature CV risk 4 Many with HoFH experience their first coronary event in childhood or adolescence 4 HeFH prevalence ranges from 1 in 200 to 1 in Individuals with HeFH can present with LDL-C levels 90 to 500 mg/dl and have premature CV risk 4 On average, individuals with HeFH experience their first coronary event at age 42 (about 20 years younger than the general population) 4 Early treatment is recommended for all individuals with FH, with a goal of reducing LDL-C levels by 50% from baseline 3 Abbreviations: CV, cerebrovascular; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, lowdensity lipoprotein cholesterol. 1. Zimmerman MP. Am Health Drug Benefits. 2015;8: ; 2. Goldstein J, et al. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995: ; 3. Bouhairie VE, et al. Cardiol Clin. 2015;33: ; 4. Turgeon RD, et al. Can Fam Physician. 2016;62:32-37.

17 laboratory tests in FH Secondary hypercholesterolemia causes Genetic diagnosis LDL Receptor activity PCSK9 levels Lp(a) levels

19 Other genetic disorders Lysosomal Acid Lipase deficiency Sitosterolemia (Phytosterolemia) lecithin cholesterol acyltransferase deficiency

21 LDL-C Overlap

22 Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia Nordestgaard B G et al. Eur Heart J 2013;34:

24 Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

heritable and mainly controlled by the apolipoprotein(a) gene [LPA] located on chromosome 6q26-27.

28 Lipoprotein (a) An LDL + apolipoprotein a Different lengths of apo a (kringles) caused by a variable number of kringle IV repeats More kringles = lower Lp(a) levels Hepatic synthesis Lp(a) plasma concentrations are highly heritable and mainly controlled by the apolipoprotein(a) gene [LPA] located on chromosome 6q KIV-2 copy number variant: 2 to >40 repeats apolipoprotein(a) LDL-like particle Koschinsky et al. Cur Opin Lipidol 2004;15:

29 LIPOPROTEIN (a): mechanisms of atherogenesis Homology with plasminogen (= impaired fibrinolysis) Binds to macrophages foam cell formation Binds to platelets (inhibition or stimulation?) Deposition of cholesterol into plaques?

30 Emerging Risk Factor Collaboration. JAMA 2009; 302:

31 Emerging Risk Factor Collaboration. JAMA 2009; 302:

32 Typical distributions of lipoprotein(a) levels in the general population. Nordestgaard B G et al. Eur Heart J 2010;31: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

34 LIPOPROTEIN (a) MEASUREMENT Quantitative Lp(a) measurements rocket immunoelectrophoresis rate and endpoint nephelometry turbidimetry radio-immuno assays enzyme immuno assays (ELISA) dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA)

35 Figure. Levels of lipoprotein(a) and risk of myocardial infarction by KIV-2 genotype. Risk of Myocardial Infarction Lipoprotein(a) (mg/dl) KIV-2 KIV-2 quartile quartile Multifactorially Hazard ratio adjusted hazard ratio (95% confidence CI) interval) st 1st 2nd 2nd 3rd 3rd Trend: p<0.001 Trend p< th 4th Trend p<0.001 Trend: p<0.001 Kamstrup et al. JAMA 2009; 301:

36 Clarke et al. New Engl J Med 2009; 361:

Lipid metabolism in familial hypercholesterolemia

Lipid metabolism in familial hypercholesterolemia Khalid Al-Rasadi, BSc, MD, FRCPC Head of Biochemistry Department, SQU Head of Lipid and LDL-Apheresis Unit, SQUH President of Oman society of Lipid & Atherosclerosis