Abstract

This is a competitive renewal application to study the genetics and metabolism of familial hypobetalipoproteinemia (FHBL). Genetic studies: In addition to our families with APOB mutations on chromosome (chr) 2, we reported on seven families with linkage of FHBL to a 2cM region on chromosome 3p21. One of our aims is to find the etiologic gene in the region by positional cloning, using DHPLC (Transgenic Wave) technology and genomic DNA sequencing for mutation detection. A third group of FHBL five families manifests no linkage with either chr 2 or 3. Genomewide genotyping is being performed in these families.
Our second aim i s to perform linkage analyses to find susceptibility regions and ultimately the gene(s). Metabolic studies: Using magnetic resonance spectroscopy, we found 5-fold increases in liver fat in FHBL subjects bearing apoB truncation mutations compared with matched controls. We have also studied the assembly of VLDL-triglycerides (TG) in these subjects. Infusions of 2H2-palmitate, quantitation of palmitate tracer/tracee ratios in plasma and in VLDL-triglycerides by gas chromatography-mass spectrometry, and kinetic modeling of the data demonstrate that a greater proportion of VLDL-TG is derived from hepatic sources than from plasma palmitate in FHBL subjects than controls. A significant correlation was found between liver fat (by MRI) and the fractional contribution of hepatic sources (r=0.90, p=0.001).
Our aim i s to extend these studies in our FHBL subjects and to patients with the metabolic Syndrome X, and to evaluate the importance of metabolic """"""""risk factors"""""""" such as body weight, insulin resistance on the extent of accumulation of liver fat in these groups.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059515-09
Application #
7007363
Study Section
Metabolism Study Section (MET)
Program Officer
Srinivas, Pothur R
Project Start
1998-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
9
Fiscal Year
2006
Total Cost
$391,700
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Sherva, Richard; Yue, Pin; Schonfeld, Gustav et al. (2007) Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families. J Lipid Res 48:2632-9
Lin, Xiaobo; Chen, Zhouji; Yue, Pin et al. (2006) A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation. Am J Physiol Gastrointest Liver Physiol 290:G1170-6
Lin, Xiaobo; Yue, Pin; Xie, Yan et al. (2005) Reduced intestinal fat absorptive capacity but enhanced susceptibility to diet-induced fatty liver in mice heterozygous for ApoB38.9 truncation. Am J Physiol Gastrointest Liver Physiol 289:G146-52
Schonfeld, G; Lin, X; Yue, P (2005) Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci 62:1372-8
Lin, Xiaobo; Yue, Pin; Chen, Zhouji et al. (2005) Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. Am J Physiol Gastrointest Liver Physiol 288:G1179-89
Yue, Pin; Tanoli, Tariq; Wilhelm, Olayinka et al. (2005) Absence of fatty liver in familial hypobetalipoproteinemia linked to chromosome 3p21. Metabolism 54:682-8
Garbow, J R; Lin, X; Sakata, N et al. (2004) In vivo MRS measurement of liver lipid levels in mice. J Lipid Res 45:1364-71
Tanoli, Tariq; Yue, Pin; Yablonskiy, Dmitriy et al. (2004) Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res 45:941-7
Chen, Zhouji; Fitzgerald, Robin L; Li, Gang et al. (2004) Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele. J Lipid Res 45:155-63
Schonfeld, Gustav (2003) Familial hypobetalipoproteinemia: a review. J Lipid Res 44:878-83

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