Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels

Abstract

Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels. This nucleoside can also participate in the early development of atherosclerosis by inhibiting the formation of foam cells via stimulation of cholesterol efflux through A2AR expressed on macrophages and reduction of the inflammatory process by activating A2AR and A2BR. Adenosine also appears to modulate intracellular cholesterol availability in Niemann-Pick type C1 disease and Alzheimer disease via A2AR and A3, respectively. Remarkably, the role of adenosine receptors in the regulation of plasma total cholesterol and triglyceride levels has been studied in animal models. Thus, an anti-atherogenic role for A2BR as well as a pro-atherogenic role of A2AR and A1 have been proposed; A3R has not been shown to participate in the control of lipid levels or the development of atherosclerosis. Surprisingly, and despite the role of A2A in the inhibition of foam cell formation among isolated cells, this receptor appears to be pro-atherogenic in mice. Remarkably, the role of adenosine receptors in human dyslipidaemia and atherosclerosis must to be elucidated. Additionally, it has been reported that increased lipid levels impair the effects of adenosine/adenosine receptors in controlling vascular tone, and we speculate on the possibility that this impairment could be due to alterations in the composition of the membrane microdomains where the adenosine receptors are located. Finally, a possible role for adenosine/adenosine receptors in the phenomena of dyslipidaemia in pregnancy has been proposed.

Effects of Coffee Intake on Dyslipidemia Risk According to Genetic Variants in the ADORA Gene Family among Korean Adults

“…The ADORA gene family has been reported to play a role in regulating the lipid profile [12]. For instance, ADORA1 deficiency in ApoE KO mice was associated with increased plasma lipid levels [22], and ADORA2B knockout mice showed increased TG and TC levels compared to the wildtype [23].…”

“…The ADORA gene family, composed of ADORA1, ADORA2A, ADORA2B, and ADORA3, are differently expressed in a tissue-specific manner and show unique properties in regulating multiple physiological statuses [7]. A recent review highlighted that the ADORA gene members are modulators of lipid availability [12]. The physiological role of the ADORAs has been reported to be associated with lipid-related diseases, including cardiovascular disease [13], coronary blood flow [14], chronic heart failure [15], atherosclerosis, and dyslipidemia [16].…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Adenosine carries out different biological effects determined by each AR on the membrane surface of specific cells or tissues (Figure 1) [43]. Initially, ARs were grouped into A 1 and A 2 receptors based on their effects in inhibiting and stimulating cyclic AMP (cAMP) in the brain [44].…”

“…Initially, ARs were grouped into A 1 and A 2 receptors based on their effects in inhibiting and stimulating cyclic AMP (cAMP) in the brain [44]. Currently, the four receptor subtypes (A 1 , A 2A , A 2B , and A 3 receptors) have been purified and successfully cloned from mammalian and nonmammalian species, particularly rats, mice, and humans [11,43]. Based upon sequence similarity and G protein-coupling specificity, A 1 and A 3 receptor share 49% sequence identity and preferentially couple to Gα i/o in the inhibition of adenylate cyclase (AC).…”

Adenosine and Adenosine A2AReceptors as Targets for the Treatment of Niemann Pick Type C Disease

“…Several observations converge to support the hypothesis that the adenosinergic system and, in particular, A 2A R may represent a ''druggable'' target for the treatment of NPC1. In fact, adenosine plays an important role in the regulation of lipid availability in cells 38 and A 2A R can reverse cholesterol transport and inhibit foam cell formation in macrophages. 39 In addition, the stimulation of A 2A Rs can increase the traffic of lysosomes to the plasma membrane through a calcium-dependent mechanism, 40 and agonists of A 2A Rs can restore altered lysosomal pH, 41 which is known to modulate calcium homeostasis.…”