Metabolism and Genetics of Hypobetalipoproteinemia

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DESCRIPTION (provided by applicant): 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 is 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 is 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.