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 acylCoA 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.Studies with isolated and cultured cells have provided evidence for the existence of a protein-facilitated component in the membrane transport of long chain fatty acids (FA) 1 in adipose(1, 2), liver (3, 4), and muscle tissues (3, 5). Among the proteins proposed to enhance FA uptake is the transmembrane protein CD36. Expression of this protein in fibroblasts, which do not endogenously express CD36, was associated with an increase in FA uptake and incorporation into phospholipids (6). This increase reflected the appearance of a saturable, phloretinsensitive component exhibiting a transport K m within the physiologic range of unbound FA concentrations (7-10 nM) (7). The distribution of CD36 favors tissues with a high metabolic capacity for FA such as adipose, heart, and skeletal muscle (8). In muscle tissues, CD36 expression is most abundant in red oxidative fibers and is up-regulated with muscle stimulation concomitant with an increase in the V max of FA transport (9). Expression is also high in tissues experiencing large fluxes of FA such as capillary endothelia, mammary epithelia (10), or epithelia of the small intestine (11).Mice null for CD36 were recently developed and found to exhibit increased serum FA, triglyce...

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Fatty acid translocase (FAT)/CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in vivo evidence has emerged for its physiologic and pathologic relevance. As these in vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.