J Lipid Atheroscler.  2020 Jan;9(1):66-78. 10.12997/jla.2020.9.1.66.

CD36 (SR-B2) as a Target to Treat Lipid Overload-Induced Cardiac Dysfunction

• Glatz JF
• Luiken JJ
• Nabben M

• KMID: 2470801
• DOI: http://doi.org/10.12997/jla.2020.9.1.66

Abstract

The heart faces the challenge of adjusting the rate of fatty acid uptake to match myocardial demand for energy provision at any given moment, avoiding both too low uptake rates, which could elicit an energy deficit, and too high uptake rates, which pose the risk of excess lipid accumulation and lipotoxicity. The transmembrane glycoprotein cluster of differentiation 36 (CD36), a scavenger receptor (B2), serves many functions in lipid metabolism and signaling. In the heart, CD36 is the main sarcolemmal lipid transporter involved in the rate-limiting kinetic step in cardiac lipid utilization. The cellular fatty acid uptake rate is determined by the presence of CD36 at the cell surface, which is regulated by subcellular vesicular recycling from endosomes to the sarcolemma. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Thus, in conditions of chronic lipid overload, high levels of CD36 are moved to the sarcolemma, setting the heart on a route towards increased lipid uptake, excessive lipid accumulation, insulin resistance, and eventually contractile dysfunction. Insight into the subcellular trafficking machinery of CD36 will provide novel targets to treat the lipid-overloaded heart. A screen for CD36-dedicated trafficking proteins found that vacuolar-type H⁺-ATPase and specific vesicle-associated membrane proteins, among others, were uniquely involved in CD36 recycling. Preliminary data suggest that these proteins may offer clues on how to manipulate myocardial lipid uptake, and thus could be promising targets for metabolic intervention therapy to treat the failing heart.

Keyword

Cluster of differentiation 36; Scavenger receptor B2; Lipid overload; Cardiac function; Cardiomyopathy

MeSH Terms

Cardiomyopathies
Diabetic Cardiomyopathies
Endosomes
Glycoproteins
Heart
Insulin Resistance
Lipid Metabolism
R-SNARE Proteins
Receptors, Scavenger
Recycling
Sarcolemma
Glycoproteins
R-SNARE Proteins
Receptors, Scavenger

Figure

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  Fig. 1 Two-photon microscopy imaging of sarcolemmal CD36 before and after insulin stimulation. Isolated rat cardiac myocytes under basal conditions (left) or after 15 minutes of incubation with 100 nM insulin (right) were incubated with anti-CD36 antibody and subsequently with a fluorescein isothiocyanate-labeled secondary antibody (green). The more intense green labeling of the sarcolemma (right photo) is due to the insulin-induced translocation of CD36 from intracellular storage depots (endosomes) to the sarcolemma. Courtesy of Dr. L.K.M. Steinbusch. CD36, cluster of differentiation 36.

• 

  Fig. 2 Scheme illustrating the similarity of the regulation of CD36-mediated LC-FA uptake and GLUT4-mediated glucose uptake by cardiomyocytes. In response to contractile activity or stimulation with insulin, both the fatty acid transporter CD36 (also designated scavenger receptor B2) and the GLUT4 translocate to the sarcolemma to increase fatty acid and glucose uptake, respectively. Note that CD36 and GLUT4 may be recruited from distinct stores within the endosomal compartment. The GLUT1 is constitutively expressed in the sarcolemma and contributes up to 25% of glucose uptake.18 CD36, cluster of differentiation 36; GULT, glucose transporter; LC-FA, long-chain fatty acids; FABPpm, plasma membrane fatty acid-binding protein; FABPc, cytoplasmic fatty acid-binding protein.

• 

  Fig. 3 Induction of lipotoxic cardiac dysfunction in an in vitro experiment. Isolated rat cardiomyocytes were incubated for 48 hours in a medium with either a low (20 µM) or high (200 µM) concentration of palmitate complexed to bovine serum albumin, in the latter condition in the absence or presence of an anti-CD36 antibody. Cellular triacylglycerol content (left panel) was assessed by thin-layer chromatography, and insulin sensitivity by western blot detection of phosphorylated Akt (middle panel). Peak sarcomere shortening was measured with a video-based imaging system from IonOptix (right panel). CD36, cluster of differentiation 36. *Significantly different from control (p<0.05).27

• 

  Fig. 4 Mechanism of lipid-induced v-ATPase inhibition and loss of insulin sensitivity in cardiac myocytes upon lipid oversupply. (1) When the supply of LC-FA is low, CD36 is primarily found in endosomes. Furthermore, the v-ATPase V0 subcomplex, which is integral to the endosomal membrane, is assembled with the cytosolic V1 subcomplex, allowing for acidification of the endosomal lumen. In this situation, the available supply of LC-FA is metabolized to meet the immediate energy demands of the myocyte. Elevated extracellular LC-FA supply triggers a series of events: (2a) increased CD36-mediated LC-FA uptake results in elevated intramyocellular LC-FA levels, causing the V1 subcomplex to dissociate; (2b) the V1 subcomplex is shifted toward the cytoplasm; (2c) the disassembly of v-ATPase leads to endosomal alkalinization; and (2d) increased endosomal pH triggers the translocation of CD36 vesicles to the sarcolemma. Upon chronic lipid oversupply, where LC-FA uptake surpasses the metabolic needs of the cell, further processes are set in motion: (3a) the lipid-induced increase in sarcolemmal CD36 feeds forward to further LC-FA uptake and progressive lipid storage (TAG); (3b) excess formation of DAG and Cer culminates into impairment of the insulin signaling cascade and, therefore, loss of insulin sensitivity.35 CD36, cluster of differentiation 36; v-ATPase, vacuolar-type H+-ATPase; LC-FA, long-chain fatty acids; FABPpm, plasma membrane fatty acid-binding protein; FABPc, cytoplasmic fatty acid-binding protein; TAG, triacylglycerol; DAG, diacylglycerol; Cer, ceramides.

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