UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Apolipoprotein E and HDL Levels

Apolipoprotein (apo) E, a key mediator of lipid transport, has three major isoforms that differ at two positions. The functional consequences of these structural differences are profound. ApoE2 is associated with type III hyperlipoproteinemia, and apoE4 with increased risk of atherosclerosis and Alzheimer's disease. ApoE3 is considered the normal isoform.

ApoE is the critical ligand in the clearance of atherogenic remnant lipoproteins by the liver. A key molecule in their initial capture or sequestration in the space of Disse is heparan sulfate proteoglycan (HSPG). Subsequent uptake by hepatocytes involves both low density lipoprotein (LDL) receptors and the HSPG/LDL receptor–related protein pathway.

We continue to study heart disease risk factors as part of our Turkish Heart Study. Compared to western Europeans or Americans, Turks have greater (25–30%) hepatic lipase activity and lower (10–15 mg/dl) levels of high density lipoprotein cholesterol (HDL-C). This striking reduction in HDL-C occurs after puberty. The mean HDL-C levels in Turkish boys drop from ~58 to 37 mg/dl and remain at 36–37 mg/dl during adulthood. The HDL-C levels in Turkish girls decrease from ~55 to 43 mg/dl and remain at 40–43 mg/dl.

We are now looking for single nucleotide polymorphic sites in genes that may be associated with lipid abnormalities and coronary artery disease. For example, cholesterol ester transfer protein (CETP) is important in reverse cholesterol transport and HDL metabolism. More than 2000 random subjects from the Turkish Heart Study were screened for the CETP TaqIB polymorphism. The rare B2B2 genotype was associated with higher HDL-C and lower CETP activity. The B1B1 genotype was associated with 5–15% lower HDL-C than the B2B2 genotype in both sexes, with an additional 8–10% decrease in smokers.

We have also assessed two sites in ABCA1 , which participates in HDL-C formation. HDL-C was 8–10% higher in men (but not in women) with the rare –14T allele than in those with the C–14T promoter polymorphism. In combination with R219K, C–14T increased HDL-C in both sexes. The rare V771M polymorphism was associated with higher HDL-C in men and, in combination with I883M, with higher HDL-C in both sexes. HDL-C levels in Turks may be modulated by an interaction between CETP polymorphisms and smoking and by ABCA1 polymorphisms.

Selected References

Mahley RW, Arslan P, Pekcan G, Pépin GM, Agaçdiken A, Karaagaoglu N, Rakicioglu N, Nursal B, Dayanikli P, Palaoglu KE, Bersot TP (2001) Plasma lipids in Turkish children: Impact of puberty, socioeconomic status, and nutrition on plasma cholesterol and HDL. J. Lipid Res. 42:1996–2006.

Bersot TP, Pépin GM, Mahley RW (2003) Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol. Am. Heart J. 146:1052–1060.

Hodoglugil U, Williamson DW, Huang Y, Mahley RW (2005) An interaction between the Taq 1B polymorphism of cholesterol ester transfer protein and smoking is associated with changes in plasma high-density lipoprotein cholesterol levels in Turks. Clin. Genet. 68:118–127.

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