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

描述（由申请人提供）：低β脂蛋白血症（HBLP）的特征是低水平的apoB（<20-50 mg/dL），apoB是低密度脂蛋白（LDL）中的主要蛋白质。申请人描述了由于apoB-67截短导致的HBLP，其中受影响的家族成员的平均LDL-C水平为39 mg/dL，HDL-C水平为65 mg/dL（比正常值高43%），并且在12年随访时，与未受影响的家族成员相比，动脉粥样硬化的发生率较低。这些发现表明，这种突变可能会阻止动脉粥样硬化的发展;因此，低LDL-C和高HDL-C水平的机制具有临床相关性。ApoB在血浆中以两种同种型存在，apoB-100，在肝脏中作为极低密度脂蛋白（VLDL）产生，apoB-100和apoB-48，在肠中作为乳糜微粒产生。杂合子apoB-67受试者有一个正常的等位基因，使apoB-100;因此，apoB-100水平将被预测为至少50%的正常;然而，他们只有24%的正常和apoB-48水平是11%的正常。对于稳定同位素，申请人已经表明，低于预期的apoB-100水平是由于VLDL apoB-100的分泌减少和催化增加以及LDL apoB-100的产生减少。申请人现在提出确定低水平apoB 48和高水平HDL-C和apoA-I的机制。申请人在19名正常受试者中的基线动力学显示：1）apoB 48库大小由分泌速率而非分解代谢分数速率确定; 2）来自肠的apoB-48的较低分泌与VLDL apoB-100的较低分泌和增加的催化剂相关;和3）HDL apoA-I和apoB 48催化剂反向相关。该资助的具体目的是：1）在16名apoB-67受试者中进行apoB和apoA-I的动力学研究，并与19名已研究的对照组进行比较; 2）确定HDL颗粒大小并确定其组成; 3）进行肠活检以测量apoB mRNA水平。待检验的假设是：1）apoB-67受试者的apoB-48分泌将降低75%，并解释了apoB-48的低水平; 2）高水平的HDL-C和apoA-I将归因于apoA-I的催化剂减少; 3）apoB-48和HDL apoA-I催化剂将负相关; 4）HDL颗粒将主要由大的、HDL 2大小的α和前α 1 -3 Lp A-I仅含有颗粒组成，并且富含胆固醇酯;和5）与对照相比，apoB-67受试者的肠apoB mRNA水平将低75%。apoB-67突变可能为低LDL-C和高HDL-C水平的机制以及降低胆固醇的新的和更好的疗法提供见解。

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.