CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes

Abstract

An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…To the best of our knowledge, the present study is the first to revealed that both exendin‐4 and saxagliptin significantly reduced lipid content in CMs both in vivo and in vitro by controlling the PPARa‐CD36 pathway, which is a major regulatory signal in cardiac FA metabolism. The long‐chain FA transporter CD36 is responsible for >60% of the cardiac FA uptake (Angin et al., 2012). Heart‐specific CD36 deficiency prevents myocardial lipid accumulation and rescues cardiac dysfunction.…”

Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate

“…1 , muscle cells did not exhibit an increase in proinfl ammatory signaling when chronically exposed to oleate, a very prevalent circulating MUFA. Furthermore, like palmitoleate, oleate was able to attenuate the proinfl ammatory effects of both palmitate and stearate based on the reduced phosphorylation of loss of I B ␣ in L6 myotubes, both events were noticeably reduced in muscle cells that had been preincubated with anti-CD36 at concentrations previously reported to inhibit CD36-mediated fatty acid uptake ( 36 ). Antibody treatment did not modify palmitoleate action, consistent with the idea that the ability of this MUFA to repress the proinfl ammatory effect of palmitate was contingent on cellular fatty acid uptake.…”

“…1 and 2 may be initiated by signaling cascades that start at the cell membrane and do not require palmitate to enter the cell. To test this possibility, we investigated the effects of an antibody that inhibits palmitate uptake via the CD36 fatty acid transporter ( 36 ). Fig.…”

CD36 Protein Influences Myocardial Ca2+ Homeostasis and Phospholipid Metabolism

“…CD36 Ϫ/Ϫ mice are protected from myocardial dysfunction consequent to excessive FA supply or impaired mitochondrial capacity, suggesting that targeting CD36 may be beneficial under these conditions (15)(16)(17)(18)(19). Conversely, CD36 deficiency eliminates the fuel flexibility that is characteristic of the healthy myocardium (20), and whether this impacts myo-cardial capability to adapt to certain stresses remains unknown.…”