ApoB and ApoA-I Kinetics in the ApoB-67 Mutation

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DESCRIPTION (provided by applicant): Hypobetalipoproteinemia (HBLP) is characterized by low levels of apoB (<20-50 mg/dL), the main protein in low-density lipoprotein (LDL). The applicant has described HBLP due to a truncated apoB-67 in which affected family members have mean LDL-C levels of 39 mg/dL and HDL-C levels of 65 mg/dL (43% higher than normals) and lower rates of atherosclerosis compared to unaffected family members at 12-year follow-up. These findings suggest that this mutation may prevent the development of atherosclerosis; therefore, mechanisms for the low LDL-C and high HDL-C levels are clinically relevant. ApoB exists in two isoforms in plasma, apoB-100, produced as very low density lipoprotein (VLDL) apoB-100 in the liver and apoB-48, produced as chylomicrons in the intestine. Heterozygous apoB-67 subjects have one normal allele making apoB-100; therefore, apoB-100 levels would be predicted to be at least 50% of normal; however, they are only 24% of normal and apoB-48 levels are 11% of normal. With stable isotopes, the applicant has shown that the lower than expected levels of apoB-100 result from decreased secretion and increased catabolism of VLDL apoB-100 and decreased production of LDL apoB-100. The applicant now proposes to determine mechanisms for the low levels of apoB48 and high levels of HDL-C and apoA-I. Baseline kinetics in 19 normal subjects by the applicant showed that: 1) apoB48 pool size is determined by secretion rate and not fractional catabolic rate; 2) a lower secretion of apoB-48 from the intestine is associated with a lower secretion and increased catabolism of VLDL apoB-100; and 3) HDL apoA-I and apoB48 catabolism are inversely related. The specific aims of this grant are to: 1) perform kinetics for apoB and apoA-I in 16 apoB-67 subjects and compare to 19 controls already studied; 2) size HDL particles and determine their composition; and 3) perform intestinal biopsies to measure apoB mRNA level. The hypotheses to be tested are: 1) apoB-48 secretion will be 75% lower in apoB-67 subjects and account for low levels of apoB-48; 2) high levels of HDL-C and apoA-I will be due to decreased catabolism of apoA-I; 3) apoB-48 and HDL apoA-I catabolism will be inversely correlated; 4) HDL particles will be primarily composed of large, HDL2-sized alpha and pre-alpha1-3 Lp A-I only containing particles and be cholesterol-ester enriched; and 5) intestinal apoB mRNA levels will be 75% lower in apoB-67 subjects compared to controls. The apoB-67 mutation may provide insights into mechanisms of low LDL-C and high HDL-C levels and new and better therapies to lower cholesterol.