Monogenic hypercholesterolemias

Important insights into CHD pathogenesis have come from the study of monogenic hypercholes-terolemias, and have led to the development of the most widely used class of lipid-lowering drugs, the HMG-CoA-reductase inhibitors (statins). Among the many known risk factors for atherosclerosis, very high low density lipoprotein (LDL) cholesterol levels are probably unique in their ability to lead to the development of premature atherosclerosis in humans in the absence of other additional risk factors. Table 24.2 summarizes the main characteristics of the known Mendelian disorders of severe hypercholesterolemia, all of which are associated with premature CHD.

Autosomal dominant hypercholesterolemias

Familial hypercholesterolemia (FH) was the first genetic disease of lipid metabolism to be clinically and genetically characterized and it represents the most common and most severe form of Mendelian hypercholesterolemia (Goldstein et al., 2001). The disease is caused by mutations in the LDL receptor (LDLR) and so far nearly 900 mutations have been identified (www.ucl.ac.uk/fh). In FH homozygotes serum levels of LDL cholesterol are very high from birth, irrespective of lifestyle, and response to treatment depends to a large extent on the type of LDLR mutation and residual LDLR activity. FH homozygotes develop severe atherosclerosis in early childhood, initially in the aortic root, causing supravalvular aortic stenosis and then involving the coronary ostia and arteries. If treatment to reduce LDL cholesterol is not initiated in early childhood or is inadequate, FH homozygotes die of myocar-dial infarction very early in life, often in the first decade (Goldstein et al., 2001; Thompson, 1999). In patients with heterozygous FH, serum LDL cholesterol levels are lower than in homozygotes and clinical prognosis depends much more on other genetic and environmental factors (Hill et al., 1991; Pimstone et al., 1998). If untreated, more than 50% of male and about 15% of female FH heterozygotes die before 60 years of age of CHD (Marks et al., 2003; Slack, 1969).

A clinically similar syndrome to FH is familial defective apolipoproteinB-100 (FDB), which results from a mutation in the LDLR binding domain of the apolipoproteinB (ApoB) gene (Soria 1989). FDB homozygotes have much lower levels of serum LDL cholesterol than FH homozygotes and the development of atherosclerotic complications is delayed (Myant, 1993). LDL cholesterol levels are lower in FDB than in FH due to lack of accumulation of cholesterol rich remnant particles, which utilize apolipoprotein E as a ligand for the LDLR (Figure 24.1) (Schaefer etal., 1997).

A new form of autosomal dominant hypercho-lesterolemia, caused by mutations in the PCSK9 gene has been recently described (Abifadel et al., 2003). The gene, residing on chromosome 1, encodes neutral apoptosis-regulated convertase 1 (NARC-1), a member of the proteinase K family of substances (Seidah et al., 2003). Some missense mutations in the PCSK9 gene have been associated with unusually severe hypercholesterolemia and

Cetp Pcsk9

Figure 24.1 Outline of lipoprotein metabolism in humans. Chylomicrons (CM) transport dietary lipids, while very low density lipoproteins (VLDL), low density lipoproteins (LDL) and the high density (HDL) lipoproteins transport endogenously synthesized lipids. Apolipoprotein (apo)B is the major structural protein of CM, VLDL and LDL, and apoA-I of HDL.

Dietary lipids are packed with apolipoproteins in the small intestine to form CM. In the circulation the core triglycerides of CM are hydrolyzed and form CM remnants. VLDL particles secreted into the plasma by the liver are triglyceride rich and undergo lipolysis to form cholesterol-rich VLDL remnants. Around half of the VLDL remnants are removed by the liver via the LDL receptor (LDLR), for which both apoE and apoB are ligands. The remainder of VLDL are further converted into LDL particles, which are cleared from the circulation by the LDLR or by the non-receptor mediated pathway. Nascent HDL during its transformation into HDL is directly involved in reverse cholesterol transport by acquiring lipids, providing an antiatherogenic function of HDL. Passage of cholesterol across the cell membrane depends on an ATP-binding cassette transporter (ABCA1), which is a cholesterol efflux regulatory protein. A significant part of the cholesterol transported to different tissues is normally returned to the liver for elimination in bile as bile acids and free cholesterol, a process for which the two ABC half-transporters: ABCG5 and ABCG8 are required. Reviewed in more detail elsewhere (Durrington, 2003; Packard and Shepherd 1999). Adapted from Shoulders et al., 2004.

CETP = cholesterol ester transfer protein; NR = non-receptor mediated transport; SRA = scavenger receptor A; SRB1 = scavenger receptor B1; FFA= free fatty acids; ARH = autosomal recessive hypercholesterolemia, a putative LDLR adaptor protein; LRP = LDL receptor-like protein.

very early CHD (Naoumova et al., 2005) due, at least in part, to overproduction of ApoB (Sun et al., 2005). Elucidation of the substrates and function of PCSK9 gene product and the mechanisms involved in the development of severe hyper-cholesterolemia will provide new insights into the metabolism of atherogenic lipoproteins and possibly novel therapeutic targets.

Table 24.2. Monogenic disorders that cause hypercholesterolemia

Plasma

Plasma

Premature

Major

Disease

Defective gene

Prevalence

LDL-C

TG

CHD risk

metabolic defect

Reference

Autosomal dominant forms

FH ("classic")

LDLR

i LDL clearance

(Goldstein et al, 2001)

Heterozygous FH

1:500

+++

- to +

+++

Homozygous FH

1:1x10s

++++++

- to +

++++++

FDB

ApoB

i LDL clearance

(Myant, 1993; Soria et al.

1989)

Heterozygous FDB

1:1000

++

-

++

Homozygous FDB

1:4x10s

++++

-

+++

fh3

PCSK9 (NARC-1)

Unknown

(Abifadel et al, 2003;

Naoumova et al, 2005;

Varret et al, 1999)

Heterozygous FH3

3 families reported

++++

- to +

++++

Homozygous FH3

2

2

2

2

Autosomal recessive forms

Autosomal recessive

ARH

~50 patients

+++++

- to +

+++++

i LDL clearance

(Arca et al, 2002; Garcia

hypercholesterolemia

reported

et al, 2001; Naoumova

(ARH)

et al, 2004)

Sitosterolemia

ABCG5 or ABCG8

~50 patients

- to +++++

-

+++++

f sterol absorption

(Berge et al, 2000; Salen

reported

i sterol secretion in

et al, 1992)

bile

Cholesterol 7a-hydroxylase

CYP7A1

3 siblings reported

++

- to ++

Unknown

i Cholesterol

(Pullinger et al, 2002)

deficiency

excretion

i LDL clearance ?

FH: familial hypercholesterolemia; FDB: familial defective apolipoprotein B; LDL: low density lipoprotein.

FH: familial hypercholesterolemia; FDB: familial defective apolipoprotein B; LDL: low density lipoprotein.

Autosomal recessive hypercholesterolemias

The recent characterization of a rare gene defect causing autosomal recessive hypercholesterolemia (ARH) (Garcia et al., 2001) has provided new information into the underlying mechanism of clathrin-mediated internalization of the LDLR. Mutations in ARH, which encodes a novel adaptor protein, prevent normal internalization of the LDLR by cultured lymphocytes and monocyte-derived macrophages, but not by skin fibroblasts (Eden et al., 2002). The clinical phenotype of ARH is similar to that of classical homozygous FH caused by defects in the LDLR gene, but is more variable and generally less severe (Naoumova et al., 2004).

Sitosterolemia is a rare but highly atherogenic disorder, characterised by the accumulation of both animal and plant sterols in the blood and tissues and development of aortic stenosis and premature CHD (Salen et al., 1992). Sitosterolemia results from a defect in sterol efflux from cells and is caused by mutations in either of two adjacent genes that encode ABC half-transporters, ABCG5 and ABCG8, expressed almost exclusively in hepa-tocytes and enterocytes (Figure 24.1) (Berge et al., 2000; Lee etal., 2001).

A hypercholesterolemic phenotype similar to that in heterozygous FH has also been reported in siblings with homozygous mutations in the gene for 7-a-hydroxylase, the first enzyme in the pathway of bile acid synthesis in the liver (Pullinger et al., 2002).

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