Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart-specific lipoprotein lipase transgenic mouse.
Lipid accumulation is associated with cardiac dysfunction in diabetes and obesity. Transgenic mice expressing non-transferable lipoprotein lipase (LpL) with a glycosylated phosphatidyl-inositol (GPI) anchor in cardiomyocytes have dilated cardiomyopathy. However, the mechanisms responsible for lipid accumulation and cardiomyopathy are not clear. Hearts from 3-month-old mice expressing GPI-anchored human LpL (hLpLGPI) mice had increased fatty acid oxidation and heart failure genes and decreased glucose transporter genes. 6-month-old mice had increased mRNA expression and activation of the apoptosis marker caspase-3. Moreover, hLpLGPI hearts had significant cytochrome c release from mitochondria to cytosol. Low density lipoprotein uptake was greater in hLpLGPI hearts, and this was associated with more intracellular apolipoprotein B (apoB). To test whether lipid accumulation in the hLpLGPI heart is reduced by cardiac expression of apoB, hLpLGPI mice were bred with transgenic human apoB (HuB)-expressing mice. Hearts of HuB/hLpLGPI mice had less triglyceride (38%) and free fatty acids (19%), secreted more apoB, and expressed less atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and more glucose transporter 4 (GLUT4). The increased mortality of the mice was abrogated by the transgenic expression of apoB. Therefore, we hypothesize that cardiac apoB expression improves cardiomyopathy by increasing lipid resecretion from the heart.
Yokoyama
Masayoshi
M
Department of Medicine, Columbia University, New York, New York 10032, USA.
Yagyu
Hiroaki
H
Hu
Yunying
Y
Seo
Toru
T
Hirata
Kumiko
K
Homma
Shunichi
S
Goldberg
Ira J
IJ
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D001055:Apolipoproteins B; D011994:Recombinant Proteins; D008071:Lipoprotein Lipase