Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia

Abstract

Background-Evidence from humans suggests that fatty acid translocase (FAT)/CD36 deficiency can lead to functionally and/or energetically compromised hearts, but the data are equivocal, and the subject remains controversial. In this report we assessed the contribution of FAT/CD36 to overall fatty acid oxidation rates in the intact heart and determined the effect of FAT/CD36 on energy metabolism during reperfusion of ischemic hearts. Methods and Results-Isolated working hearts from wild-type and FAT/CD36-knockout (KO) mice were perfused with Krebs-Henseleit solution containing 0..5 mmol/L calcium, and 100 U/mL insulin at a preload pressure of 11.5 mm Hg and afterload pressure of 50 mm Hg. Hearts were aerobically perfused for 30 minutes or aerobically perfused for 30 minutes, followed by 18 minutes of global no-flow ischemia and 40 minutes of aerobic reperfusion. Rates of fatty acid oxidation in FAT/CD36-KO hearts were significantly lower than in wild-type hearts at both concentrations of palmitate (0.4 or 1.2 mmol/L). In addition, hearts from FAT/CD36-KO mice displayed a compensatory increase in glucose oxidation rates. On aerobic reperfusion after ischemia, cardiac work of FAT/CD36-KO hearts recovered to the same extent as wild-type hearts. Conclusions-FAT/CD36-deficient

CD36: Implications in cardiovascular disease

“…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). Even at high work loads, CD36 KO mouse hearts performed as well, if not better than wild type hearts because of full compensation for energy by glucose.…”

“…Whatever the mechanism, absence of CD36 affects fatty acid uptake by various tissues, including adipocytes and muscle, and this leads to measurable phenotype (Febbraio, et al, 1999). 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).…”

“…Using an isolated perfused heart system in collaboration with the lab of Jason Dyck, we showed that CD36 plays an important role in fuel substrate choice in the heart (Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004). In the absence of CD36, the heart, which normally derives most of its energy from fatty acids, instead relies more heavily on glucose.…”

“…We now know that the broad expression pattern of CD36 is mirrored by its equally broad list of functions. In the last 5 years, CD36 has figured prominently in the fields of cardiovascular function and disease ,Kuang, Febbraio, Wagg, Lopaschuk, & Dyck, 2004, parasitology (Franke-Fayard, et al, 2005), cancer biology (Huang, et al, 2004), Alzheimer's disease (Moore, et al, 2004), stroke (Cho, et al, 2005) angiogenesis (Simantov, Febbraio, & Silverstein, 2005), diabetes (Corpeleijn, et al, 2006, Lepretre, et al, 2004, platelet biology (Englyst, Taube, Aitman, Baglin, & Byrne, (2003), muscle function and metabolism (Koonen, Glatz, Bonen and Luiken, 2005), and even food choice (Laugerette, et al, 2005). The creation of the CD36 knock out (KO) mouse and subsequent crossing to other murine mutants has enabled many of these studies (Febbraio, et al, 1999).…”

AMP-activated protein kinase control of energy metabolism in the ischemic heart

“…At the sarcolemmal membrane of the working heart, fatty acid translocase (FAT/CD36) has been shown to account for as much as 50% of the fatty acid acid taken up into the cell and subsequently used for oxidation. 14 A key site of control for the transport of fatty acids into the mitochondria is the enzyme carnitine palmitoyl transferase 1 (CPT-1), which is located on the outer mitochondrial membrane. This enzyme is inhibited by malonyl-CoA, the levels of which are indirectly regulated by AMPK.…”