Role of Keratinocytes GPR109A and COX-2 in Nicotinic Acid and Mono-methyl Fumarate Induced Flushing
Hanson, Julien ; ; et al
Poster (2010, July 17)Detailed reference viewed: 26 (2 ULg)
Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice.
Hanson, Julien ; ; et al
in Journal of Clinical Investigation (2010), 120(8), 2910-9
The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome ... [more ▼]
The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a-/- mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin. [less ▲]Detailed reference viewed: 85 (18 ULg)
An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81.
; ; et al
in Cell Metabolism (2010), 11(4), 311-9
Lactate is an important metabolic intermediate released by skeletal muscle and other organs including the adipose tissue, which converts glucose into lactate under the influence of insulin. Here we show ... [more ▼]
Lactate is an important metabolic intermediate released by skeletal muscle and other organs including the adipose tissue, which converts glucose into lactate under the influence of insulin. Here we show that lactate activates the G protein-coupled receptor GPR81, which is expressed in adipocytes and mediates antilipolytic effects through G(i)-dependent inhibition of adenylyl cyclase. Using GPR81-deficient mice, we demonstrate that the receptor is not involved in the regulation of lipolysis during intensive exercise. However, insulin-induced inhibition of lipolysis and insulin-induced decrease in adipocyte cAMP levels were strongly reduced in mice lacking GPR81, although insulin-dependent release of lactate by adipocytes was comparable between wild-type and GPR81-deficient mice. Thus, lactate and its receptor GPR81 unexpectedly function in an autocrine and paracrine loop to mediate insulin-induced antilipolytic effects. These data show that lactate can directly modulate metabolic processes in a hormone-like manner, and they reveal a new mechanism underlying the antilipolytic effects of insulin. [less ▲]Detailed reference viewed: 53 (6 ULg)
Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis
; ; et al
in Journal of Biological Chemistry (2009), 284(33), 21928-33Detailed reference viewed: 44 (6 ULg)