Based on these findings we set
Based on these findings, we set out to identify GPR109A agonists capable of biasing the receptor's signaling towards the functional anti-lipolytic and presumed therapeutic response, and away from the flushing side-effect pathways. Indeed, using recombinantly expressed GPR109A, two classes of compounds eliciting differential, or biased signaling were characterized . The first class of compounds, which included niacin, coupled the receptor to inhibition of adenylyl cyclase, MAP kinase activation and receptor internalization. The second class of agonists, which included a partial agonist MK-0354, was capable only of inhibiting adenylyl cyclase and failed to activate other signaling pathways. When tested in appropriate animal models, compounds from the first class produced both antilipolytic as well as flushing responses, while the second class of compounds functioned as antilipolytics, but were devoid of the flushing response, consistent with the data from Walters et al. indicating that beta-arrestin pathway mediates flushing, but not antilipolytic response to niacin . When tested in humans, MK-0354 acutely reduced plasma free fatty Zinc Pyrithione levels without causing a significant flushing response, but surprisingly failed to produce any meaningful changes in plasma lipid profile, including HDL-c, LDL-c and triglycerides after 28days of dosing , . This led to the hypothesis that, in addition to inhibition of adenylyl cyclase, one or more of the additional GPR109A signaling cascades induced by niacin may be required to achieve desirable effects on serum lipids, which led to the development of MK-1903, a compound retaining the full spectrum of niacin-induced GPR109A signaling activities in recombinant GPR109A-expressing cells . Clinical testing of MK-1903 in humans demonstrated that while administration of this compound led to a reduction in plasma free fatty acid levels as well as the expected flushing response, it also did not modulate levels of HDL-c, LDL-c and triglycerides in a clinically meaningful fashion . These studies raised serious doubts regarding the “free fatty acid (FFA) hypothesis” that niacin-mediated inhibition of free fatty acid production in adipose is responsible for desirable changes in plasma lipid profile. The ‘final nail in the coffin’ of the FFA hypothesis may be the demonstration that niacin administration in mice lacking GPR109A did not result in reduction of plasma free fatty acid levels yet produced effects on HDL-c, LDL-c and triglycerides similar to those seen in control animals . Taken together, these studies suggest that GPR109A is not the sole molecular target responsible for niacin-mediated changes in plasma lipids. The prevailing view that the clinical benefits of niacin are attributable to its lipid-modifying properties has been challenged in an elegant study by Lukasova et al., which demonstrated that niacin possesses GPR109A-mediated anti-atherosclerotic activity that is independent from its anti-dyslipidemic properties , . In a mouse model of atherosclerosis, niacin was shown to inhibit disease development without affecting the plasma lipid profile. These effects were demonstrated to be mediated by GPR109A expressed on immune cells, since transplantation of bone marrow from GPR109A deficient mice abrogated the beneficial effects of niacin in wild type mice. Among immune cells, macrophages recruited to the sites of developing atherosclerotic lesions are established as key players in the progression of the disease process, particularly through development into lipid-laden foam cells, which can serve as epicenters for thrombus formation. Two distinct mechanisms for GPR109A-mediated effects on macrophage function in atherosclerotic disease were implicated in the study by Lukasova et al. First, GPR109A expressing macrophages were detected in atherosclerotic lesions and niacin treatment reduced the number of macrophages in these lesions. A role for GPR109A in macrophage recruitment is supported by the observation that niacin is able to modulate chemokine (MCP-1) induced recruitment of macrophages into the peritoneal cavity in the wild type but not GPR109A deficient mice. Second, it was demonstrated that niacin upregulates the expression of ABCG1, a transporter involved in reverse cholesterol transport, in macrophages from wild type but not GPR109A deficient mice. Accordingly, treatment with niacin was shown to up-regulate cholesterol efflux in macrophages from the wild type, but not GPR109A-deficient mice. Similarly, in a previous study by Rubic et al., niacin treatment of a monocytic cell line was shown to upregulate expression of cholesterol transporter ABCA1 as well as other genes involved in reverse cholesterol transport, namely PPARγ and the scavenger receptor CD36 .