Chapter 115

## Abstract

Abstract

1. VLDL and chylomicrons, which transport triglycerides to peripheral tissues via the bloodstream, are major lipoprotein secretory products of the liver and intestine, respectively. Each class of these lipoproteins contains a protein of very-high molecular weight (a B apolipoprotein) that is essential for the secretion of the lipoprotein particle and that has very high affinity for lipids, remaining with the lipoprotein complex throughout its metabolic processing in plasma or lymph.

2. There are two translation products of a single structural gene for B apolipoproteins. In humans, the exclusive B apoprotein of VLDL and LDL is apo B-100, a single polypeptide chain of 4536 amino acid residues and the full-length translation product of the gene. The predominant species of apo B in chylomicrons is apo B-48, a single chain of 2152 amino acid residues identical to the N-terminal portion of apo B-100. This protein is translated from an edited mRNA transcript containing a single base substitution that produces a stop codon corresponding to residue 2153 of apo B-100. Several disorders are now recognized in which the secretion of apo B-containing lipoproteins or the structure of apo B itself is abnormal.

3. Abetalipoproteinemia (MIM 200100) is an autosomal recessive disorder characterized by the virtual absence of VLDL and LDL from plasma. Fat malabsorption is severe and triglyceride accumulation occurs in enterocytes and, to some extent, in liver. Acanthocytosis of erythrocytes is common. Spinocerebellar ataxia with degeneration of the fasciculus cuneatus and fasciculus gracilis, peripheral neuropathy, degenerative pigmentary retinopathy, and ceroid myopathy all appear to be secondary to defects of transport of tocopherol in blood. It is possible that mechanisms underlying the failure to secrete VLDL and chylomicrons differ among kindreds. However, intracellular accumulation of B protein points to defects in the processing of B apoproteins or impairment of the assembly or secretion of triglyceride-rich lipoproteins. The first molecular defect now recognized is the absence of activity of microsomal triglyceride transfer protein, a factor critical to the lipidation of B proteins. Treatment involves reduction of dietary fat to prevent steatorrhea and supplementation with tocopherol to prevent progression of the neuromuscular and retinal degenerative disease.

4. In the homozygous state, clinical manifestations of familial hypobetalipoproteinemia (HBL) (MIM 107730) are indistinguishable from those of abetalipoproteinemia: acanthocytosis, neuromuscular disability, and malabsorption. Clinically, this disorder is distinguished from recessive abetalipoproteinemia by the appearance of hypolipidemia in heterozygotes. The defects underlying this disorder involve the gene for apo B in most cases. A number of mutations have been described that lead to the secretion of truncated forms of the protein. In some cases, the phenotype does not cosegregate with apo B haplotypes. Defects affecting the rate of synthesis or the rate of removal of apo B are emerging.

5. Fat malabsorption and the absence of chylomicrons in plasma after fat ingestion characterize chylomicron retention disease (MIM 246700). Apo B-100 is found in LDL; however, total LDL levels are about half of normal. Acanthocytosis and neurologic manifestations occur in some patients. The defect appears to be recessive. Large numbers of particles resembling nascent chylomicrons crowd the enterocyte, accompanied by high levels of apo B-48, suggesting a specific defect in the secretion of chylomicrons.

6. Apo B-100 carries a ligand domain for the LDL receptor. Several mutations in apo B-100 affecting the binding affinity of LDL for the receptor have been identified. Levels of LDL in plasma are increased in many but not all individuals who bear one mutant allele. The hyperlipidemia is usually less severe than that observed with LDL receptor defects because LDL precursors can be endocytosed via the ligand in apolipoprotein E.

7. Familial combined hyperlipidemia is probably the most prevalent genetically determined disorder of lipoproteins now recognized. It carries a significantly increased risk of coronary arteriosclerosis. It appears to be an autosomal dominant trait with high penetrance that leads to increased levels of apo B-100 and elevated levels of VLDL, LDL, or both in plasma. The phenotypic pattern can shift among these types over time. Kinetic studies suggest that increased production of apo B-100 may be a common underlying metabolic characteristic.

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