Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation

Abstract

AimsThe type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.Methods and resultsHearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.ConclusionsDiabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

The Implication of PGC-1α on Fatty Acid Transport across Plasma and Mitochondrial Membranes in the Insulin Sensitive Tissues

“…Some authors speculate that the upregulation of the nuclear receptor transcription factor PPARα and its coactivators PGC-1α/β is one of the preliminary requirements for metabolic switch from glucose to FA consumption in IR and diabetic hearts (Schilling, 2015 ; Lee et al, 2017 ). This agrees with an increased level of PPARα as well as the total (+38%) and sarcolemmal (+26%) FAT/CD36 content in the diabetic animal hearts (Mansor et al, 2017 ). On the contrary, lowered PGC-1α expression was observed in diabetic human blood and myocardium (Fabregat-Andres et al, 2016 ) as well as in the animal models of T2DM (ob/ob mice) and diabetic dyslipidemia (db/db mice) (Buchanan et al, 2005 ).…”

“…Interestingly, PPARα and FAT/CD36 deficient mice [α-myosin heavy chain (MHC)-PPARα/CD36 −/− ] were not only protected from lipid imbalance in the myocardium, but also demonstrated an enhanced glucose uptake and FATP1 gene expression (Yang et al, 2007 ). Nevertheless, direct inhibition of plasma membrane FAT/CD36 by sulfo-N-succinimidyl oleate was sufficient to restore normal substrate metabolism and prevent lipotoxicity (Mansor et al, 2017 ). PPARγ overexpression in transgenic mice contributed to cardiac dysfunction encompassing an increase in FAT/CD36 level, FA uptake and intracellular lipid accumulation with rosiglitazone treatment even aggravating the lipotoxic effects.…”

Assessing the optimal preparation strategy to minimize the variability of cardiac pyruvate dehydrogenase flux measurements with hyperpolarized MRS

“…The rats were housed in a 12:12 hour light/dark cycle in animal facilities at the University of Oxford. A model of Type II diabetes mellitus (T2DM) characterized by hyperglycaemia, hyperinsulinemia and hyperlipidaemia was induced based on a previously published protocol . Briefly, 24 age‐matched female Wistar rats (11 weeks of age at start of study) were divided into two groups: a control group receiving normal chow (12% calories from fat, 22% from protein and 66% from carbohydrates) and a T2DM group receiving a high fat diet for nine weeks (60% calories from fat, 35% from protein, 5% from carbohydrate).…”

Vitamin E: Regulatory Role on Signal Transduction

“…By down‐regulating CD36 expression and by triggering internalization of CD36, vitamin E can reduce the accumulation of intracellular lipids and contribute to the protective effects of αT and αTP against lipotoxicity occurring during high‐fat induced development of atherosclerosis, inflammation, obesity, NASH, and the metabolic syndrome (Fig. ) . The activation of CD36 can affect a variety of metabolic functions relevant for lipid homeostasis, as demonstrate with the growth hormone releasing peptides hexarelin that regulates LXRα, PGC1α/PPARγ, INSIG1/2, and fatty acid metabolic enzymes in monocytes/macrophages, liver and adipose tissue .…”