CD36 actions in the heart: Lipids, calcium, inflammation, repair and more?

Abstract

CD36 is a multifunctional immuno-metabolic receptor with many ligands. One of its physiological functions in the heart is the high-affinity uptake of long-chain fatty acids (FAs) from albumin and triglyceride rich lipoproteins. CD36 deletion markedly reduces myocardial FA uptake in rodents and humans. The protein is expressed on endothelial cells and cardiomyocytes and at both sites is likely to contribute to FA uptake by the myocardium. CD36 also transduces intracellular signaling events that influence how the FA is utilized and mediate metabolic effects of FA in the heart. CD36 transduced signaling regulates AMPK activation in a way that adjusts oxidation to FA uptake. It also impacts remodeling of myocardial phospholipids and eicosanoid production, effects exerted via influencing intracellular calcium (iCa(2+)) and the activation of phospholipases. Under excessive FA supply CD36 contributes to lipid accumulation, inflammation and dysfunction. However, it is also important for myocardial repair after injury via its contribution to immune cell clearance of apoptotic cells. This review describes recent progress regarding the multiple actions of CD36 in the heart and highlights those areas requiring future investigation. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

Keywords: AMPK; Fatty acid; LKB1; Mitochondria; Signaling; Uptake.

Fig. 1. Model for heart FFA uptake

FFAs carried by albumin or generated from VLDL lipolysis by LpL enter the heart via CD36 while FFAs generated from chylomicrons enter mostly via non-CD36-mediated mechanisms. FFAs induce CD36 internalization possibly via promoting its ubiquitination (red tags). The FAs might internalize within CD36-rich vesicles. LpL also creates remnant particles that bind to lipoprotein receptors for uptake of core lipids.

Fig. 2. Cardiac metabolic flexibility is lost in Cd36KO mice

2-[¹⁸F]fluorodeoxyglucose (FDG) uptake by the heart is rapidly reduced by fasting in WT mice but not in Cd36KO mice. Hearts were harvested for counting at 0, 6 and 16h after start of fasting. **p<0.001

Fig. 3. Heart CD36 is likely to function in FFA transfer both at the level of endothelial cells and cardiomyocytes

FABP: FA binding protein, FATP: FA transport protein, HSPG: Heparan sulfate proteoglycan, GPIHBP1: glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1.

Fig. 4. CD36 association with Top mitochondria

Top: Hearts of 16h fasted mice have higher CD36 content in sarcolemma (left) and in isolated mitochondria (right), *p<0.05. Bottom: Hela cells expressing CD36 (green) show areas of CD36 co-localization with the mitochondrial anion channel VDAC (red), (40X, Axiovert 200M) (Samovski D, unpublished data).

Fig. 5. CD36 inhibits LKB1 and this is reversed by palmitic acid

Top: LKB1 (green) is mostly in the nucleus in CD36 (red) expressing myotubes (BSA control). Bottom: Palmitic acid (300 uM, 2:1 with BSA, for 15 min) relocates LKB1 to cytosolic CD36-positive vesicular structures (inset, arrows point to overlap between CD36 and LKB1). From Samovski D et al. 2015 [1]

Fig. 6. AMPK regulation

CD36 is in a molecular complex in proximity to Fyn, LKB1 and AMPK. CD36 suppresses AMPK keeping it quiescent by allowing Fyn inhibition of LKB1. This inhibition is reversed by CD36 ligation of palmitic acid (PA), which activates LKB1 and AMPK by dissociating Fyn.