Update on the molecular biology of dyslipidemias

doi:10.1016/j.cca.2015.10.033

Clinica Chimica Acta

Volume 454, 15 February 2016, Pages 143-185

https://doi.org/10.1016/j.cca.2015.10.033 Get rights and content

Highlights

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Dyslipidemias are important determinants of cardiovascular disease
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Inherited familial dyslipidemias are usually caused by mutations in genes that regulate lipid metabolism: LDLR, APOB, LDLRAP1, PCSK9, LPL, APOC2, APOAV, LMF1, GPIHBP1, MTP, ANGPTL3, ANGPTL4, CETP, apoAI, LCAT
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Dysbetalipoproteinemia stems from dysfunctional apoE
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In contrast to the rare familial syndromes, in most patients dyslipidemias are the result of multiple genetic variants, with secondary factors eg obesity and metabolic syndrome playing a role in clinical presentation
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In future, genetic assessment may identify patients at risk for cardiovascular disease and lead to the development of individualised treatment protocols

Abstract

Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. Although secondary factors play a role in clinical expression, dyslipidemias have a strong genetic component. Familial hypercholesterolemia is usually due to loss-of-function mutations in LDLR, the gene coding for low density lipoprotein receptor and genes encoding for proteins that interact with the receptor: APOB, PCSK9 and LDLRAP1. Monogenic hypertriglyceridemia is the result of mutations in genes that regulate the metabolism of triglyceride rich lipoproteins (eg LPL, APOC2, APOA5, LMF1, GPIHBP1). Conversely familial hypobetalipoproteinemia is caused by inactivation of the PCSK9 gene which increases the number of LDL receptors and decreases plasma cholesterol. Mutations in the genes APOB, and ANGPTL3 and ANGPTL4 (that encode angiopoietin-like proteins which inhibit lipoprotein lipase activity) can further cause low levels of apoB containing lipoproteins. Abetalipoproteinemia and chylomicron retention disease are due to mutations in the microsomal transfer protein and Sar1b-GTPase genes, which affect the secretion of apoB containing lipoproteins. Dysbetalipoproteinemia stems from dysfunctional apoE and is characterized by the accumulation of remnants of chylomicrons and very low density lipoproteins. ApoE deficiency can cause a similar phenotype or rarely mutations in apoE can be associated with lipoprotein glomerulopathy. Low HDL can result from mutations in a number of genes regulating HDL production or catabolism; apoAI, lecithin: cholesterol acyltransferase and the ATP-binding cassette transporter ABCA1. Patients with cholesteryl ester transfer protein deficiency have markedly increased HDL cholesterol. Both common and rare genetic variants contribute to susceptibility to dyslipidemias. In contrast to rare familial syndromes, in most patients, dyslipidemias have a complex genetic etiology consisting of multiple genetic variants as established by genome wide association studies. Secondary factors, obesity, metabolic syndrome, diabetes, renal disease, estrogen and antipsychotics can increase the likelihood of clinical presentation of an individual with predisposed genetic susceptibility to hyperlipoproteinemia. The genetic profiles studied are far from complete and there is room for further characterization of genes influencing lipid levels. Genetic assessment can help identify patients at risk for developing dyslipidemias and for treatment decisions based on ‘risk allele’ profiles. This review will present the current information on the genetics and pathophysiology of disorders that cause dyslipidemias.

Section snippets

Overview of lipid metabolism

Understanding the mechanisms of lipoprotein metabolism has important clinical indications as lipoproteins are risk factors for atherosclerosis. In both liver and intestine, apolipoprotein B (apoB) is cotranslationally translocated to the endoplasmic reticulum (ER) lumen where facilitated by microsomal transfer protein (MTP), lipid is added to apoB to form primordial apoB containing particles. In humans apoB48 is secreted exclusively by the intestine in chylomicrons and apoB100 is secreted

Clinical presentation

Elevated plasma levels of LDL cholesterol have been shown to be a risk factor for the development of atherosclerosis and associated ischemic heart disease (IHD). In men, a rise in total cholesterol from 5.2 to 6.2 mmol/L is associated with a threefold increased risk of death from IHD [50]. Raised serum cholesterol and LDL cholesterol are characteristic of familial hypercholesterolemia (FH, OMIM 143890). In the pre-genomic era the commonly used system for classification of dyslipidemias was based

HDL and cardiovascular disease

Numerous population studies have shown that an inverse relationship exists between plasma HDL and IHD risk. Two HDL subclasses can be separated by ultracentrifugation: HDL₂ is less dense and relatively lipid rich, HDL₃ is more dense and relatively protein rich. On agarose gel the HDL separates into α migrating particles which represent the majority of circulating HDL and preβ particles which represent poorly lipidated HDL. Further resolution can be achieved by a 2-dimensional electrophoretic

Secondary dyslipidemias

Secondary non-genetic factors associated with dyslipidemias include obesity, metabolic syndrome, alcohol consumption, diabetes, renal disease, pregnancy (mainly in the third trimester), paraproteinemia, systemic lupus erythematosus and medications that include corticosteroids, oral estrogen, tamoxifen, thiazides, non-cardioselective beta blockers, bile acid sequestrants, cyclophosphamide, antiretroviral drugs and second generation antipsychotic reagents. People who develop secondary

Treatment of dyslipidemias

The possibility of secondary dyslipidemias needs to be considered before initiating therapy. The mechanism of action of common cholesterol lowering drugs in routine use is summarized below.

(i) Statins: Statins competitively inhibit HMGCR reductase activity. The reduction in intracellular cholesterol increases LDLR expression on the hepatocyte cell surface and increases extraction of LDL cholesterol from blood.

(ii) Bile acid sequestrants: By binding to bile acids the drugs remove the bile acids

Future directions

Severe dyslipidemia, a decrease or increase in serum lipoproteins is usually a simple monogenic disorder showing a Mendelian inheritance. More frequently dyslipidemia results from the cumulative effects of several genes combined with environmental and metabolic stressors such as high calorie intake, metabolic syndrome, diabetes and certain drugs. Despite our increased understanding of molecular basis of dyslipidemias, much remains to be learned. Genetic profiles are far from complete and there

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Update on the molecular biology of dyslipidemias

Highlights

Abstract

Section snippets

Overview of lipid metabolism

Clinical presentation

HDL and cardiovascular disease

Secondary dyslipidemias

Treatment of dyslipidemias

Future directions

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

J. Lipid Res.

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

Clin. Chim. Acta

Clin. Chim. Acta

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

Cell Metab.

J. Biol. Chem.

J. Nutr.

Atherosclerosis

J. Clin. Lipidol.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

J. Biol. Chem.

Am. J. Hum. Genet.

Lancet

Lancet

J. Biol. Chem.

J. Biol. Chem.

J. Lipid Res.

Exp. Cell Res.

Genomics

J. Lipid Res.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Arch. Biochem. Biophys.

J. Lipid Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Activation of phosphatidylcholine-sterol acyltransferase by human apolipoprotein E isoforms

Eur. J. Biochem.

Intracellular trafficking and secretion of VLDL

Arterioscler. Thromb. Vasc. Biol.

Recent advances in physiological lipoprotein metabolism

Clin. Chem. Lab. Med.

Intrahepatic role of exchangeable apolipoproteins in lipoprotein assembly and secretion

Arterioscler. Thromb. Vasc. Biol.

Affects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in helathy young men

J. Lipid Res.

HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events

Clin. Chem.

Give me A5 for lipoprotein hydrolysis

J. Clin. Invest.

Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism

Curr. Opin. Lipidol.

Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo

J. Clin. Invest.

Complexities of plasma apolipoprotein C-III metabolism

J. Lipid Res.

Topology of human lipoprotein E3 uniquely regulates its diverse biological functions

Proc. Natl. Acad. Sci.