Lipoproteins: Genetic Disorders


The primary function of plasma lipoproteins is to transport newly synthesised or dietary lipids in the circulation; these water‐insoluble substances include triacylglycerol, cholesterol and fat‐soluble vitamins. Mutations in genes for the many enzymes, receptors and structural proteins that regulate lipoprotein metabolism and transport are often detrimental to health, and may increase the amount of normal lipoproteins, result in accumulation of abnormal lipoproteins or cause lipoprotein deficiencies. Some defects increase the risk of coronary heart disease, whereas other deficiency disorders cause neurological and/or gastrointestinal symptoms. Genetic disorders of lipoprotein metabolism highlight the importance of lipid transport and metabolism in normal human physiology.

Key Concepts

  • Normal regulation of plasma lipoprotein metabolism is critical for transport of lipids and fat‐soluble vitamins in the circulation.

  • Once secreted from cells in the liver or intestine, lipoproteins undergo many complex metabolic changes in the blood circulation brought about by enzymes and their cofactors, exchange factors and cell‐surface receptors.

  • Variation in the genes for these proteins can alter their function and cause changes in the composition, concentration and/or function of plasma lipoproteins that are frequently deleterious to health.

  • Several defects in lipoprotein metabolism result in increased risk of premature coronary heart disease because of cholesterol deposition in the blood vessels, whereas others lead to neurological symptoms due to deficiency of fat‐soluble vitamins.

  • The inheritance pattern varies: most known lipoprotein disorders are monogenic, with either autosomal dominant inheritance, where heterozygous carriers are affected or autosomal recessive inheritance, where heterozygous carriers are apparently unaffected. Some dominantly inherited disorders have a gene dosage effect, where homozygous individuals are more severely affected than heterozygous ones.

  • Some gene variants only have a marked physiological effect in a particular genetic or environmental background, so not all carriers are affected.

  • Families exist who have a clinical phenotype characteristic of a known monogenic disorder, but who have no detectable defect in the known causal genes; this suggests that novel genes still remain to be identified that influence lipoprotein metabolism.

  • One of the commonest inherited disorders, familial combined hyperlipidaemia, is not monogenic and requires several gene variants to be present for symptoms to be manifest. These variants are also unlikely to be the same for all families.

Keywords: lipid metabolism; atherosclerosis; hyperlipidaemia; coronary heart disease; mutations; fat‐soluble vitamin deficiency

Figure 1.

Metabolism of apolipoprotein B (ApoB)‐containing lipoproteins. (TAG) and ApoB100 are synthesized in liver and assembled to form very low‐density lipoproteins (VLDL) by a mechanism that requires microsomal triacylglycerol transfer protein (MTP). In the circulation the TAG is hydrolysed by (LPL), which requires ApoCII as cofactor, with the formation of intermediate density lipoprotein (IDL). Excess surface components (phospholipid, cholesterol and non‐ApoB apoproteins) are transferred to HDL (see Figure ). TAG in IDL is further hydrolysed by LPL and (HL), to finally form low‐density lipoproteins (LDL), which accumulate in plasma. LDL is removed from the circulation mainly by LDL receptor (LDLR)‐mediated uptake and degradation in the liver. LDL in the circulation is liable to oxidative modification, thus allowing it to be taken up by macrophage scavenger receptors. (CM) are synthesized and secreted from the intestine following ingestion of fat and contain ApoB48 rather than ApoB100. Once in the circulation, they suffer a similar fate to VLDL. (CMR) are cleared rapidly from the circulation by (CMRR) on the liver. Genetic disorders are known that influence all these processes.

Figure 2.

Metabolism of high‐density lipoproteins (HDL). HDL in plasma is formed from several sources, including excess surface material generated during the hydrolysis of triacylglycerol (TAG)‐rich lipoproteins (see Figure ), as well as by direct secretion of HDL precursors, sometimes called ‘nascent HDL’, from the liver and intestine. Nascent HDL acquires free cholesterol from cells by interaction with a cell‐surface cholesterol efflux protein called ATP‐binding cassette transporter A1 (ABCA1). The free cholesterol on the surface of HDL is rapidly esterified by the enzyme lecithin cholesterol acyltransferase (LCAT) which requires Apo‐A‐I, a major HDL apolipoprotein, as cofactor. The cholesteryl ester (CE) is hydrophobic and thus forms the core of the HDL particle and HDL can then take up more free cholesterol on its surface, eventually forming CE‐rich HDL. Exchange and transfer of lipids between lipoproteins is catalysed by the (CETP), allowing exchange of HDL CE for TAG in VLDL, forming an HDL particle that is richer in TAG. TAG in HDL is removed from the particles by hepatic lipase (HL) activity in the liver, without degradation of the HDL. Similarly CE can be removed from HDL by interaction with HDL receptors (SR‐B1) in liver. Thus HDL functions to transfer cholesterol from peripheral tissues to the liver, a process referred to as reverse cholesterol transport. Genetic disorders are known that influence all these processes.



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Further Reading

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Soutar AK (1993) Investigation and diagnosis of disorders of lipoprotein metabolism. In: Rapley R and Walker MR (eds) Molecular Diagnostics. Oxford: Blackwell Scientific.

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Soutar, Anne K(Sep 2009) Lipoproteins: Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002279.pub2]