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 associa tion between CD36 deficiency and defective myocardial uptake of the fatty a cid analog 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) has been reported. To determine whether this association represents a causal li nk and to assess the physiological role of CD36, we compared tissue uptake and metabolism of two iodinated fatty acid analogs BMIPP and 15-(p-iodophen yl) pentadecanoic acid (IPPA) in CD36 null and wild type mice. We also inve stigated the uptake and lipid incorporation of palmitate by adipocytes isol ated from both groups. Compared with wild type, uptake of BMIPP and IPPA wa s reduced in heart (50-80%), skeletal muscle (40-75%), and adipose tissues (60-70%) of nub mice. The reduction was associated with a 50-68% decrease i n label incorporation into triglycerides and in 2-3-fold accumulation of la bel in diglycerides, Identical results were obtained from studies of [H-3]p almitate uptake in isolated adipocytes, The block in diglyceride to triglyc eride conversion could not be explained by changes in specific activities o f the key enzymes long chain acyl-CoA synthetase and diacylglycerol acyltra nsferase, 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 h eart, skeletal muscle, and adipose tissues and that CD36 deficiency in huma ns 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. Th e membrane transport step may represent an important control site for fatty acid metabolism in vivo.