Genetics of Dyslipidemia

Profound mortality rates, due to cardiovascular disease, are a worldwide problem. Cardiovascular disease results from complications of a silent and chronic arterial disease: atherosclerosis. The challenge for the practitioner is adapting diagnostic and therapeutic responses to prevent this common and complex disease.
Dyslipidemia, are disorders of the metabolism of soluble transporters of lipids in extracellular spaces of the human body (including blood), called lipoproteins. They are major cardiovascular risk factors, causally related with atherosclerosis and are themselves multifactorial diseases, resulting from interactions between genetic and environmental factors.
The study of genetic factors has recently taken a new path with the study of DNA as an experimental object. More than fifty genes of lipoprotein metabolism have been identified in both their physiological actions and their contribution to the pathogenesis of human dyslipidemia. The diversity of observations has refined our current knowledge of the control of lipid metabolism and energy homeostasis in living organisms beyond the limits of the cardiovascular system (e.g., brain, immune system, and development). These studies have given way to a shake-up of former phenotypic classifications, distinguishing new entities, defining targeted therapeutic strategies, providing a basis for different patterns of disease distribution in human populations.

I- The Metabolism of Lipoproteins.- 1.1- Historical Landmarks.- 1.1.1- Cholesterol: a « Janus-Faced » molecule.- 1.1.2- The pathological descriptions of the 19th century.- 1.1.3- From lipido-proteinic « cenapses » to apolipoproteins.- 1.1.4- The concept of molecular disease.- 1.2- Lipids are essential components for living cells.- 1.2.1- Fatty acids derivatives.- 1.2.2- lsoprenoid derivatives.- 1.3- Lipoproteins: soluble carriers of lipids in extracellular spaces.- 1.3.1- Structure and functions of lipoproteins.- 1.3.2- Lipoproteins accross the evolution of living species.- 1.4- The Metabolism of Lipoproteins.- 1.4.1- The general architecture of lipoprotein metabolism.- + The Exogenous Pathway.- + The Endogenous Pathway.- + The Reverse Pathway.- 1.4.2- Regulations of Lipoprotein Metabolism.- + By exogenous sources of energy.- + By endogenous sensors of energy.- 1.5- Lipids and Atherosclerosis: The Causal Link.- + Pathological and biological evidence.- + Epidemiological and clinical evidence.- 1.6- Heterogeneity of Dyslipidemia.- 1.6.1- The phenotypic heterogeneity of dyslipoproteinemia.- 1.6.2- Genetic heterogeneity of dyslipidemia.- II- Genes of Lipoprotein Metabolism.- 2.1- Genes of the endogenous pathway.- 2.1.1- The LDL receptor: a gene for familial hypercholesterolemia.- 2.1.2- Apolipoprotein B: a single locus for opposite diseases.- 2.1.3- Microsomal-triglyceride Transfer Protein (MTP), a locus for abetalipoproteinemia.- 2.1.4- Lipoprotein Lp(a), a mysterious candidate for atherosclerosis.- 2.1.5- HMGCoA reductase, the rate limiting enzyme of the mevalonate pathway.- 2.1.6- Scavenger receptors.- 2.1.6.1- Scavenger receptors class A: molecular flypapers for modified lipoproteins.- 2.1.6.2- CD36, a multifunctional receptor for fatty acids and thrombospondin, scavenging oxidized lipoproteins.- 2.2- Genes controlling Triglyceride-rich lipoprotein metabolism.- 2.2.1- Lipases.- 2.2.11- Lipoprotein Lipase, the rate limiting enzyme for triglyceride-rich lipoproteins.- 2.2.12- Hepatic Lipase, a lipase for lipoprotein remodeling.- 2.2.13- Other Lipases.- 2.2.2- Apolipoproteins.- 2.2.21- Apolipoprotein C-II, an activator of lipoprotein lipase.- 2.2.22- Apoliprotein C-I, a modulator of lipoprotein catabolism.- 2.2.23- Apolipoprotein E, the major apolipoprotein for intermediate lipoproteins.- 2.2.3- Receptors.- 2.2.31- LRP, a multifunctional receptor for intermediate lipoproteins.- 2.2.32- Megalin, an ancient member of the LDL receptor gene family expressed in the kidney.- 2.2.33- VLDL Receptor (LR8), a multifunctional receptor with species-dependent requirements.- 2.3- Genes of the Reverse Pathway of lipoprotein metabolism.- 2.3.1- Apolipoproteins.- 2.3.11- Apolipoprotein A-I, a major component of HDL.- 2.3.12- Apoliprotein C-III, a modulator for triglyceride-rich lipoprotein catabolism.- 2.3.13- Apolipoprotein A-IV, a component of intestinal lipoproteins.- 2.3.14- Apolipoprotein A-II, a modulator of HDL metabolism.- 2.3.2- Circulating Enzymes and Transfer Proteins for Lipoprotein Remodeling.- 2.3.21- Lecithin Cholesterol Acyl transferase (LCAT), a rate limiting enzyme for HDL metabolism.- 2.3.22- Cholesteryl Ester Transfer Protein (CETP), a « points man» of lipoprotein metabolism.- 2.3.23- Phospholipid Transfer Protein (PLTP), a major component of HDL formation in plasma.- 2.3.3- Receptors.- 2.3.31- ABC-1, or cholesterol efflux regulatory protein, a gene for Tangier Disease and Familial hypoalphalipoproteinemia.- 2.3.32- Scavenger Receptor class B-1 (SR-BI), a multifunctional receptor for the selective uptake of cholesterol.- 2.3.33- Cubilin, a receptor for HDL in the kidney.- 2.4- Other Regulatory Pathways of Lipoprotein Metabolism.- 2.4.1- The Traffic of Intracellular Lipids.- 2.4.11- Lipid tafficking in cellular compartments.- + Niemann Pick Disease type C.- + Lysosomal Acid Lipase.- + Acyl-CoA: Cholesterol acyl transferases (ACAT).- + Intracellular fatty acid trafficking.- 2.4.12- Nuclear coordinators of intracellular energy resources.- + SREBPs (Sterol Responsive Element Binding Proteins).- + PPARs (Peroxisome Proliferator Activated Receptors).- + LXR (Liver X Receptor), FXR (Farnesoid X Receptor).- + Lamins A/C.- 2.4.2- The Biosynthesis of Bile Acids.- 2.4.3- Other Apolipoproteins.- 2.4.4- Anti-toxic and Anti-oxidative Protection.- III- The Genetic Basis of Dyslipidemias.- 3.1- The Genetic Architecture of Lipoprotein Metabolism.- 3.1.1- The functionality of candidate genes.- 3.1.11- Levels of functional significance of candidate genes.- 3.1.12- The redundancy of candidate genes.- 3.1.13- The multifunctionality of candidate genes.- 3.1.2- The driving forces of lipoprotein metabolism.- 3.2- The Candidate Gene Approach.- 3.2.1- In human disorders of lipoprotein metabolism.- 3.2.11- Identifying the disease causing mutation in inherited dyslipidemia.- 3.2.12- A redefinition of inherited dyslipidemia.- 3.2.13- The evidence of genetic interactions.- 3.2.14- Identifying risk alleles for complex diseases in populations.- 3.2.15- Genetic determinants of dyslipidemia in populations.- 3.2.2- The candidate gene approach in experimental models of dyslipidemia.- 3.2.21- In vitro studies and cell cultures.- 3.2.22- In vivo studies and animal models.- 3.2.3- Clinical issues of the candidate gene approach.- 3.2.31- Applications in current clinical care.- 3.2.32- Corrective gene therapy.- 3.2.4- Present limitations to the candidate gene approach.- 3.3- Novel Genes, Novel Approaches.- 3.3.1- Identifying novel genes of lipoprotein metabolism.- 3.3.11- Positional cloning of novel genes.- 3.3.12- Expression cloning of novel genes.- 3.3.13- In silico cloning of novel genes.- 3.3.2- Novel approaches to identify novel mechanisms of human dyslipidemia.- Conclusion.- References.