The role of CD36 in cardiovascular disease

Abstract

CD36, also known as the scavenger receptor B2, is a multifunctional receptor widely expressed in various organs. CD36 plays a crucial role in the uptake of long-chain fatty acids, the main metabolic substrate in myocardial tissue. The maturation and transportation of CD36 is regulated by post-translational modifications, including phosphorylation, ubiquitination, glycosylation, and palmitoylation. CD36 is decreased in pathological cardiac hypertrophy caused by ischemia-reperfusion and pressure overload, and increased in diabetic cardiomyopathy and atherosclerosis. Deficiency of CD36 alleviates diabetic cardiomyopathy and atherosclerosis, while overexpression of CD36 eliminates ischemia-reperfusion damage, together suggesting that CD36 is closely associated with the progression of cardiovascular diseases and may be a new therapeutic target. This review summarizes the regulation and post-translational modifications of CD36 and evaluates its role in cardiovascular diseases and its potential as a therapeutic target.

CD36 as a target for metabolic modulation therapy in cardiac disease

“…In 1993, CD36 was shown to facilitate cellular uptake of long-chain fatty acids, the predominant fuel for many tissues throughout the body with a high rate of fatty acid metabolism, such as cardiac muscle [10,11]. CD36 facilitates both transendothelial fatty acid transport [12] and fatty acid uptake into cardiomyocytes [6,7] and is responsible for >70% of the rate of fatty acid uptake and oxidation in contracting myocardium [6]. CD36 is a transmembrane protein that undergoes extensive co-translational and posttranslational modifications, including glycosylation, palmitoylation, ubiquitination, and phosphorylation [13].…”

“…During reperfusion, the transporters initially remain relocated to allow glucose to be used for replenishment of glycogen stores while preventing intracellular lipid overload so as to protect the heart should another ischemic insult occur. Chronic ischemia of the heart causes a downregulation of CD36 expression [7,29], which is generally reported as being harmful for functional recovery from ischemic episodes [29][30][31]. Although not the total cellular pool of CD36, but rather the portion present at the sarcolemma determines the rate of fatty acid uptake, a small CD36 pool may limit the dynamic interplay of substrate transporters (in particular CD36 and GLUT4) and that compromise the rapid changes in myocellular substrate preference required to sustain the phases of an ischemic insult (i.e.…”

“…Studies performed in the last two decades have shown that the transmembrane glycoprotein CD36, which facilitates long-chain fatty acid uptake into cardiac myocytes, is primarily responsible for the proper regulation of myocardial lipid metabolism. Thus, in the healthy heart the presence and activity of CD36 in the sarcolemma appears to be closely adjusted to the cellular need for fatty acids, avoiding both too low uptake rates (risk of energy deficit) and too high uptake rates (risk of lipotoxicity) [6,7]. In line with the dynamic nature of cardiac energy metabolism, whereby changes in demand may occur almost instantaneously, the sarcolemmal presence and activity of CD36 can be adapted on a short timescale.…”

CD36 Senses Dietary Lipids and Regulates Lipids Homeostasis in the Intestine

“…In patients with hyperglycemia and/or hyperlipidemia, the CD36 expression is significantly increased in vascular lesions and kidneys compared with control subjects ( Shu et al, 2020 ). In duodenal mucosa biopsies from human, the CD36 expression is also positively correlated with increasing body mass index (BMI), suggesting the dysregulation of CD36 responses to fat in obesity ( Little et al, 2014 ).…”

“…Since a patient with CD36 deficiency was found in Japan in the 1990s, numerous studies have reported that the patients with CD36 deficiency had the typical metabolic features of MetS, such as dyslipidemia, including postprandial hypertriglyceridemia, insulin resistance, and hypertension (Love-Gregory and Abumrad, 2011). These phenotypes have also been observed in CD36 knockout (CD36KO) mice (Shu et al, 2020). In addition, one strain of spontaneously hypertensive rats lacks CD36 and shows metabolic phenotypes of insulin resistance and high free fatty acid (FFA) levels, which are ameliorated by the transgenic overexpression of CD36 (Aitman et al, 1999;Pravenec et al, 2001).…”