The Metabolic Impact of Congenital Heterozygous ApoC-III Deficiency in Humans

Summary

Principal Investigator: TONI ILANA POLLIN
Abstract: DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the leading cause of death in the United States and is a major complication of type 2 diabetes (T2DM). Dyslipidemia, characterized by elevated low density lipoprotein cholesterol (LDL-C) and triglyceride levels and decreased high density lipoprotein cholesterol (HDL-C) levels, is associated with increased risk of CAD. The high TG/ low HDL-C phenotype is particularly prevalent in individuals with insulin resistance or T2DM. Apolipoprotein C-III (apoC-III), an 8.8 kDa protein component of both triglyceride-rich lipoproteins (TRLs) and HDL particles, inhibits lipoprotein lipase activity and hepatic uptake of TRLs. ApoC-III may also enhance very low density lipoprotein (VLDL) assembly and secretion, but the findings on this based on animal models and human studies are conflicting. In addition, apoC-III activates inflammatory signaling pathways, a cardiovascular risk factor of emerging importance. We recently provided evidence that apoC-III deficiency is cardioprotective by identifying a null mutation found in ~5% of the Lancaster Old Order Amish that reduces apoC-III levels by ~50% and confers favorable lipid profiles and less coronary calcification. The mutation appears rare or absent in the general population but has reached a relatively high prevalence in the Amish by a founder effect. While these recent findings strongly implicate direct apoC- III lowering as a promising therapeutic intervention, the enhanced lipolytic activity conferred by apoC-III reduction could theoretically promote disease risk by increasing visceral and muscle fat stores, which would be expected to promote insulin resistance. Alternatively, the enhanced flux of fatty acids into peripheral tissues may promote sufficient compensatory increases in fatty acid oxidation to make direct lowering of apoC-III levels a suitable target in the prevention of cardiovascular disease in insulin resistant individuals. To enhance our understanding of the metabolic effects of decreased availability of apoC-III and the role apoC-III plays in VLDL secretion in humans, we are proposing to compare individuals with heterozygous apoC-III deficiency to their non-deficient relatives to (1) evaluate the effect of apoC-III defiency on glucose and insulin metabolism and fat distribution;(2) evaluate the effect of apoC-III defiency on lipid and lipoprotein turnover;and (3) evaluate the effect of apoC-III deficiency on fat cells and their function. PUBLIC HEALTH RELEVANCE: Heart disease is a leading cause of death and disability in the United States. People who have an inborn deficiency of a protein called apoC-III appear to have a reduced risk of developing heart disease, suggesting that reducing the amount of apoC-III made in other individuals could be a useful treatment or prevention for heart disease, especially in people with diabetes. This project will look more closely at the effects of the deficiency on human metabolism to better understand the function of the apoC-III protein and its potential as a drug target.
Funding Period: 2011-01-14 - 2015-12-31
more information: NIH RePORT

Top Publications

  1. pmc A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates
    Ioanna Tachmazidou
    Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
    Nat Commun 4:2872. 2013
  2. pmc Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response
    Ping An
    Department of Genetics Division of Statistical Genomics Campus Box 8506, Washington University School of Medicine, 4444 Forest Park Blvd, St Louis, MO, 63108, USA
    Hum Genet 133:919-30. 2014
  3. pmc Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes
    Jessica S Albert
    From the Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine J S A, L M Y A, R B H, T I P, U T S, S C, S S, J R O, D W G, J C M, A R S, C S, C M D, and the Geriatrics Research and Education Clinical Center D W G, A S R, A R S, C S, Department of Radiology and Nuclear Medicine R J B, and the Veterans Affairs VA Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine A S R, Baltimore VA Medical Center all in Baltimore and the Department of Medicine, Columbia University, New York W S B
    N Engl J Med 370:2307-15. 2014

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
  3. Regulation of Metabolism by Dietary Sterols
    SHAILENDRA BHANUBHAI PATEL; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates
    Ioanna Tachmazidou
    Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
    Nat Commun 4:2872. 2013
    ..This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance...
  2. pmc Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response
    Ping An
    Department of Genetics Division of Statistical Genomics Campus Box 8506, Washington University School of Medicine, 4444 Forest Park Blvd, St Louis, MO, 63108, USA
    Hum Genet 133:919-30. 2014
    ..Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted...
  3. pmc Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes
    Jessica S Albert
    From the Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine J S A, L M Y A, R B H, T I P, U T S, S C, S S, J R O, D W G, J C M, A R S, C S, C M D, and the Geriatrics Research and Education Clinical Center D W G, A S R, A R S, C S, Department of Radiology and Nuclear Medicine R J B, and the Veterans Affairs VA Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine A S R, Baltimore VA Medical Center all in Baltimore and the Department of Medicine, Columbia University, New York W S B
    N Engl J Med 370:2307-15. 2014
    ..Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders...

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
    ..The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL. ..
  3. Regulation of Metabolism by Dietary Sterols
    SHAILENDRA BHANUBHAI PATEL; Fiscal Year: 2013
    ..Some data from animal studies indicate improvement in atherosclerosis, but aggravation of stroke. These studies are important because they may help guide nutritional advice for a very large proportion of the patient population. ..