Lipid metabolism in familial hypercholesterolemia

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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)

4

5 Biosynthesis of cholesterol In the cytosol + ER Precursor - acetyl CoA from: The reducing agent - NADPH 1. The β-oxidation of fatty acids - from PPP 2. The oxidation of ketogenic amino acids Energy for synthesis 3. The pyruvate dehydrogenase reaction - hydrolysis of CoA and ATP

6 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.

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

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

9 Composition of lipoproteins

10 Apoproteins 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

11 Lipoproteins - metabolism

12 Metabolism of VLDL, IDL and LDL

13 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

14 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

15 Modification of LDL LDL Apo B-100 Derivatization: Aldehydes Glucosylation eg. diabetes Oxidation: Degradation of B-100 by reactive oxygen species Derivatized LDL Oxidized LDL

16 The Scavenger Receptor: Clearance of modified LDL by macrophages Macrophage Macrophage Foam Cell Scavenger receptor (SR-A1) Oxidized LDL Lipid droplets Fatty streaks

17 LDL and Atherosclerosis Fitting the pieces together Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL Monocyte oxldl Endothelial cells Artery wall oxldl (stimulates cytokine secretion) Macrophage Macrophage foam cell Smooth muscle cell proliferation

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

19

20

21 Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia

22

23

24

25 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:

26 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?

27 Emerging Risk Factor Collaboration. JAMA 2009; 302:

28 Emerging Risk Factor Collaboration. JAMA 2009; 302:

29

30 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)

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