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

Summary

Principal Investigator: Francine Welty
Affiliation: Harvard University
Country: USA
Abstract: [unreadable] 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.
Funding Period: 1997-08-15 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. pmc Role of the estrogen and progestin in hormonal replacement therapy on apolipoprotein A-I kinetics in postmenopausal women
    Stefania Lamon-Fava
    Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research, Center on Aging, Tufts University, Boston, MA 02111, USA
    Arterioscler Thromb Vasc Biol 26:385-91. 2006
  2. pmc The association between soy nut consumption and decreased menopausal symptoms
    Francine K Welty
    Division of Cardiology, Beth Deaconess Medical Center, Boston, Massachusetts 02215, USA
    J Womens Health (Larchmt) 16:361-9. 2007
  3. pmc Effect of body mass index on apolipoprotein A-I kinetics in middle-aged men and postmenopausal women
    Francine K Welty
    Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
    Metabolism 56:910-4. 2007
  4. pmc Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women
    Melita M Nasca
    Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA
    Am J Cardiol 102:84-6. 2008
  5. pmc High-resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures macrophage burden in atherosclerosis
    Kunio Morishige
    Donald W Reynolds Cardiovascular Clinical Research Center at Harvard Medical School, Boston, MA, USA
    Circulation 122:1707-15. 2010
  6. ncbi LC-MS-based method for the qualitative and quantitative analysis of complex lipid mixtures
    Ulf Sommer
    Mass Spectrometry Resource, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
    J Lipid Res 47:804-14. 2006

Detail Information

Publications6

  1. pmc Role of the estrogen and progestin in hormonal replacement therapy on apolipoprotein A-I kinetics in postmenopausal women
    Stefania Lamon-Fava
    Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research, Center on Aging, Tufts University, Boston, MA 02111, USA
    Arterioscler Thromb Vasc Biol 26:385-91. 2006
    ..Hormonal replacement therapy (HRT) affects plasma HDL cholesterol levels, with estrogen increasing HDL cholesterol levels and progestins blunting this effect. This study was designed to assess the mechanism responsible for these effects...
  2. pmc The association between soy nut consumption and decreased menopausal symptoms
    Francine K Welty
    Division of Cardiology, Beth Deaconess Medical Center, Boston, Massachusetts 02215, USA
    J Womens Health (Larchmt) 16:361-9. 2007
    ..Epidemiological studies suggest a low incidence of hot flashes in populations that consume dietary soy. The present study examined the effect of soy nuts on hot flashes and menopausal symptoms...
  3. pmc Effect of body mass index on apolipoprotein A-I kinetics in middle-aged men and postmenopausal women
    Francine K Welty
    Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
    Metabolism 56:910-4. 2007
    ..Sixty-two percent of the variability in PR and 71% of the variability in FCR were due to BMI in men and only 3% and 23%, respectively, in women. In conclusion, BMI has a significant effect on apo A-I PR and FCR in men but not in women...
  4. pmc Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women
    Melita M Nasca
    Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA
    Am J Cardiol 102:84-6. 2008
    ....
  5. pmc High-resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures macrophage burden in atherosclerosis
    Kunio Morishige
    Donald W Reynolds Cardiovascular Clinical Research Center at Harvard Medical School, Boston, MA, USA
    Circulation 122:1707-15. 2010
    ..Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies...
  6. ncbi LC-MS-based method for the qualitative and quantitative analysis of complex lipid mixtures
    Ulf Sommer
    Mass Spectrometry Resource, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
    J Lipid Res 47:804-14. 2006
    ..The methods described should be easily adaptable to most modern MS instrumentation...