Temporary Inhibition of p53 for Reduced Side Effects in Anticancer Therapy

30 August, 1999

Transport of Plasma Lipoproteins and New Targets for Drug Development

Elevated plasma levels of apolipoprotein B (apoB)-containing lipoproteins constitute a major risk factor for the development of coronary heart disease. In the rare recessively inherited disorder abetalipoproteinemia (ABL), the production of apoB-containing lipoproteins is abolished, despite no abnormality of the apoB gene. Recently it was found that the gene encoding a microsomal triglyceride-transfer protein (MTP; chromosome 4q22-24) is mutated in both alleles of all affected individuals (Narcisi TM et al, 1996: uid=96065017). MTP is a heterodimeric lipid protein localized in the endoplasmic reticulum of hepatocytes and enterocytes, and composed of the ubiquitous multifunctional protein, protein disulﾞde isomerase, and a unique 97-kDa subunit. In fact, mutations (deletions and missense Arg540His) that lead to the absence of a functional 97-kDa subunit cause ABL, characterized by a defect in the assembly and secretion of apoB-containing lipoproteins (Rehberg EF et al, 1996: uid=97094705). In this disease, plasma apoB-containing lipoproteins, namely VLDL (very low density lipoprotein, containing B48 or B100) and LDL (low density lipoprotein), are virtually absent. Plasma cholesterol levels are ca 40 mg/dl and plasma triglyceride levels are less than 10 mg/dl in the patients, whereas normal adults have levels of 180-220 and 100-150 mg/dl, respectively. Clinically, affected people have fat malabsorption and have triglyceride accumulation in enterocytes and the liver, with symptoms such as spinocerebellar ataxia and peripheral neuropathy.
A related genetic disease, hypolipoproteinemia, is caused by mutations in apoB, and heterozygous people have ca 50% levels of apoB-containing lipoproteins. No clinical ABL symptoms are observed here, and individuals with hypobetalipoproteinemia tend to have prolonged life span. With an irreversible photoaffinity inhibitor, it was shown previously (Jamil H et al, 1998: uid=9684748) that apoB secretion was reduced in proportion to the in situ inhibition of MTP activity, indicating that MTP-mediated lipid transfer is limiting in the assembly and secretion of apoB-containing lipoproteins in hepatic cells. These ﾞndings indicate that controlled use of MTP inhibitors may be therapeutically useful in reducing levels of atherogenic lipoproteins.

Another interesting story is being developed for the metabolism and transport of plasma high-density lipoprotein (HDL). There are 3 recent reports (Brooks-Wilson A et al, 1999: uid=10431236; Bodzioch M et al, 1999: uid=10431237; Rust S et al, 1999: uid=10431238) on Tangier disease (TD) and the familial mutation of its locus at chromosome 9q31. Tangier disease was first discovered nearly 40 years ago in two siblings living on Tangier Island. TD is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density cholesterol (HDL-C) and deposition of cholesteryl esters in the reticulo-endothelial system, and with hepatosplenomegaly, enlargement of tonsils and lymph nodes and peripheral neuropathy. In heterozygotes, HDL-C levels are about one-half those of normal individuals. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors, and In contrast to normal macrophages, those from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. The TD locus has been mapped to chromosome 9q31. This was further refined to the gene ABC1 on chromosome 9q22-31, encoding a member of the ATP-binding cassette (ABC) transporter family. Full-length cDNAs were cloned and sequenced in unrelated families to find seven different mutations including a 1-bp deletion in exon 13 and an in-frame insertion-deletion in exon 12.

ABC1 may transport cholesterol from within the cell to outside as HDL cholesterol particles that are carried to the liver for recycling in the body. ABC1 is mutated in familial HDL deficiency syndrome (FHA) as well as in TD thus these diseases seem allelic. A high risk of coronary disease in FHA due to low HDL levels might now be viewed for developing drugs that protect against heart attack by targeting ABC1 and thus increasing HDL cholesterol levels in the blood.

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