CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease

Abstract

The multifunctional membrane glycoprotein CD36 is expressed in different types of cells and plays a key regulatory role in cellular lipid metabolism. CD36 facilitates the cellular uptake of long-chain fatty acids, mediates lipid signaling, and regulates storage and oxidation of lipids in various tissues with active lipid metabolism. CD36 deficiency leads to marked impairments in peripheral lipid metabolism, which consequently impacts on the cellular utilization of multiple different fuels, due to the integrated nature of metabolism. The functional presence of CD36 at the plasma membrane is regulated by its reversible subcellular recycling from and to endosomes, and is under the control of mechanical, hormonal and nutritional factors. Aberrations in this dynamic role of CD36 are causally associated with various metabolic diseases, in particular insulin resistance, diabetic cardiomyopathy, and cardiac hypertrophy. Recent research in cardiac muscle has disclosed the endosomal proton pump v-ATPase as a key enzyme regulating subcellular CD36 recycling and being the site of interaction between various substrates to determine cellular substrate preference. In addition, evidence is accumulating that interventions targeting CD36 directly or modulating its subcellular recycling are effective for the treatment of metabolic diseases. In conclusion, subcellular CD36 localization is the major adaptive regulator of cellular uptake and metabolism of long-chain fatty acids, and appears a suitable target for metabolic modulation therapy to mend failing hearts.

Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms

“…Altogether these data support the notion that these therapeutic bounties are driven by the agonistic stimulation of myocardial and extra-myocardial CD36 and/or GHSR1a receptors by activating survival pathways, downregulating fibrogenic cytokines, and optimizing energetic homeostasis shunts that cooperate in cellular survival (Hosoda, 2022;Shu et al, 2022;Glatz et al, 2023). Whether these cytoprotective and anti-fibrotic effects are solely consequent to the stimulation of GHS-R1a has been debated (Yuan et al, 2021) and is beyond the scope of our study.…”

Preventing the Fatty Acid-Transporter CD36 From Taking its Toll on the Heart

“…In their previous research, the authors had shown that palmitate entry in the cells through endocytosis of membrane-derived vesicles containing CD36 led to the inhibition of the endosomal proton pumping activity of v-ATPase (vacuolar-type H + -ATPase) and resulted in the alkalinization of endosomes. 5 The consequence is that deacidified endosomes can no longer serve as CD36 storage compartment and CD36 is translocated back to the membrane where it interacts with the TLR4 (Toll-like receptor 4) triggering an inflammatory response to lipid overload; see also Glatz et al 6 for a recent review on these mechanisms and a broader view on the regulatory role of CD36 in cellular lipid metabolism. In the present study, the authors also identify the C18:1-enriched diacylglycerols as the main harmful lipid mediators of lipid-induced cardiomyopathy.…”