Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice

Abstract

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...

CD36: Implications in cardiovascular disease

“…In the absence of CD36, the heart, which normally derives most of its energy from fatty acids, instead relies more heavily on glucose. This confirmed our studies with the radio labeled tracers 125 I-BMIPP (a non-metabolizable fatty acid analog), 125 I-IPPA (a metabolizable fatty acid analog) and 8-fluorodeoxyglucose (a glucose analog), which were initiated because of the observation that CD36 KO mice have fasting hypoglycemia (Coburn, Knapp, Febbraio, Beets, Silverstein, & Abumrad, 2000). Under normal and high fat conditions, we found that the CD36 KO mouse heart is entirely compensated in terms of ATP and acylCoA fatty acids by utilization of glucose (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004).…”

“…CD36 KO mice have a fasting hypoglycemia and different energy substrate use in heart (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004). Uptake of fatty acid analogs was specifically reduced in muscle and adipocytes of mice, and has been shown to be reduced in heart of CD36-deficient humans (Coburn, Knapp, Febbraio, Beets, Silverstein, & Abumrad, 2000,Watanabe, et al, 1998,Hwang, et al, 1998,Tanaka, et al 2001). …”

Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology

“…Transgenic mice overexpressing CD36 had reduced blood lipid levels (Aitman et al, 1999). CD36-null mice showed reduced fatty acids uptake in various tissues (Coburn et al, 2000). DPP4 is identical to T-cell activation antigen CD26 (Koch and Shows, 1980) and to adenosine deaminase complexing protein 2 (Morrison et al, 1993).…”

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

“…Indeed, recent evidence demonstrates that the membrane protein CD36 (fatty acid translocase), which is a facilitator of long-chain fatty acids (Coburn et al, 2000), is deficient in a rat model of human metabolic syndrome X (Aitman et al, 1999).…”