Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice.
The transmembrane protein CD36 has been identified in isolated cell studies as a putative transporter of long chain fatty acids. In humans, an association between CD36 deficiency and defective myocardial uptake of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid (BMIPP) has been reported. To determine whether this association represents a causal link and to assess the physiological role of CD36, we compared tissue uptake and metabolism of two iodinated fatty acid analogs BMIPP and 15-(p-iodophenyl) pentadecanoic acid (IPPA) in CD36 null and wild type mice. We also investigated the uptake and lipid incorporation of palmitate by adipocytes isolated from both groups. Compared with wild type, uptake of BMIPP and IPPA was reduced in heart (50-80%), skeletal muscle (40-75%), and adipose tissues (60-70%) of null mice. The reduction was associated with a 50-68% decrease in label incorporation into triglycerides and in 2-3-fold accumulation of label in diglycerides. Identical results were obtained from studies of [(3)H]palmitate uptake in isolated adipocytes. The block in diglyceride to triglyceride conversion could not be explained by changes in specific activities of the key enzymes long chain acyl-CoA synthetase and diacylglycerol acyltransferase, which were similar in tissues from wild type and null mice. It is concluded that CD36 facilitates a large fraction of fatty acid uptake by heart, skeletal muscle, and adipose tissues and that CD36 deficiency in humans is the cause of the reported defect in myocardial BMIPP uptake. In CD36-expressing tissues, uptake regulates fatty acid esterification at the level of diacylglycerol acyltransferase by determining fatty acyl-CoA supply. The membrane transport step may represent an important control site for fatty acid metabolism in vivo.
Coburn
C T
CT
Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794-8661, USA.
Knapp
F F
FF
Febbraio
M
M
Beets
A L
AL
Silverstein
R L
RL
Abumrad
N A
NA
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D005227:Fatty Acids / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007462:Iodobenzenes / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011995:Recombination, Genetic; D014018:Tissue Distribution
D018955:CD36 Antigens; D005227:Fatty Acids; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; C049338:iodofiltic acid; C025391:omega-(4-iodophenyl)pentadecanoic acid