The ketone body receptor HCA is most

The ketone body receptor HCA2 is most likely not active under normal conditions, since local levels and plasma levels of ketone bodies such as β-HB are too low to activate the receptor. However, overnight fasting or prolonged starvation results in plasma levels of the ketone body in the millimolar range [40], which are sufficient to fully activate HCA2. It has long been known that β-HB, which is synthetized in the liver from FFAs derived from lipolysis in adipocytes, inhibits lipolysis during starvation [41], and it has been hypothesized that HCA2 mediates this effect [42]. In this model, increased β-HB levels during starvation induce a negative feedback regulation by inhibiting their own formation through activating HCA2 and reducing lipolysis and FFA formation in adipocytes in an HCA2-dependent manner (Figure 1B). This mechanism may be of relevance, as it ensures against excessive loss of stored triglycerides during periods of food shortage [42]. HCA3, which is only expressed in adipocytes of higher primates, may serve a very similar function, as it is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. Under conditions of high β-oxidation rates, such as fasting, plasma concentrations of 3-hydroxy-octanoic Amonafide receptor reach levels sufficient to activate HCA312, 43. Before HCA2 was recognized as a receptor for a ketone body, it was shown to be the adipocyte receptor mediating the antilipolytic effects of the antiatherogenic drug nicotinic acid 14, 15, 16. The HCA2-mediated strong antilipolytic effect of nicotinic acid was for a long time believed to be responsible for the antiatherogenic effects of nicotinic acid; nicotinic acid is also able to decrease plasma levels of low-density lipoprotein (LDL) cholesterol and to increase the levels of high-density lipoprotein (HDL) cholesterol [44]. The prevailing model to explain the link between this HCA2-mediated antilipolytic activity and changes in plasma cholesterol levels was based on the assumption that the decreased formation and release of FFAs from adipocytes result in a reduced hepatic production of triglycerides and very-low-density lipoprotein (VLDL), and a subsequent decrease in the level of LDL cholesterol [44]. The reduced exchange of triglycerides and cholesterol esters between VLDL/LDL and HDL particles, mediated by cholesterol ester transfer protein, would then result in an increase in HDL cholesterol levels 45, 46. Studies using other synthetic agonists of HCA2 have shown that HCA2 mediates antilipolytic effects in adipocytes but is not involved in the regulation of HDL cholesterol plasma levels. It has therefore been concluded that nicotinic acid-induced increase in HDL cholesterol plasma level does not require HCA2 but depends on alternative mechanisms [47]. These data as well as the increasing evidence that an elevation of plasma HDL cholesterol levels may not necessarily have a beneficial effect on cardiovascular morbidity and mortality [48] have raised doubts about whether the antilipolytic effects mediated by HCA2 are responsible for the antiatherogenic activity of nicotinic acid. However, there is renewed interest in the pharmacological inhibition of adipocyte lipolysis through activation of HCA2 and also HCA1 as an approach to reduce insulin resistance in type 2 diabetic patients [49]. This is based on the observation that partial inhibition of lipolysis improves glucose metabolism and insulin sensitivity without altering fat mass [50]. However, it seems difficult to achieve long-term glycemic control in type 2 diabetic patients by treatment with an HCA2 receptor agonist [51]. There is also evidence that HCA2 is expressed in pancreatic islets mediating inhibition of insulin secretion 52, 53, but it needs to be shown whether this mechanism is of relevance when treating patients with HCA2 agonists.
Parallel to the reports suggesting that the antilipolytic effects mediated by HCA2 are not responsible for the antiatherogenic activity of nicotinic acid, evidence emerged that nicotinic acid can reduce the progression of atherosclerosis independently from changes in plasma lipid levels 54, 55, and that these effects are mediated by activation of HCA2 in bone marrow-derived cells [54]. The antiatherogenic and anti-inflammatory effects of nicotinic acid were accompanied by a reduced infiltration of the vessel wall by HCA2-expressing immune cells, such as macrophages and neutrophils 54, 55. Macrophages are a likely mediator of this effect, because nicotinic acid can significantly inhibit macrophage chemotaxis, cytokine production, and LDL cholesterol uptake, while enhancing the efflux of cholesterol to HDL particles, in an HCA2-dependent manner 54, 56. These effects may be enhanced by adiponectin, which is secreted from adipocytes in response to nicotinic acid-induced HCA2 activation 57, 58. Thus, the HCA2-mediated anti-inflammatory effects are an important mechanism underlying the antiatherogenic effects of nicotinic acid. Despite the fact that nicotinic acid has well-proven antiatherogenic effects which, to a considerable part, are mediated by HCA2, clinical trials using an extended release form of nicotinic acid in addition to an optimal treatment regimen with statins have not shown any additional benefit 59, 60. In these trials a slow release form of nicotinic acid at a relatively low dose was used to keep dermal side effects, such as flushing, low [61]. It has been noted that this may have led to a reduced efficacy also with regard to the wanted effects and that it is still possible that plain nicotinic acid or synthetic ligands of HCA2 given at appropriate doses have beneficial effects in the treatment of dyslipidemia and the prevention of cardiovascular disease even when given in addition to statins 61, 62.