Cholesterol is essential for all animal life but high levels of cholesterol – when associated with low density lipoprotein (LDL) – are linked to an increased risk of atherosclerosis, heart disease and stroke. Circulating cholesterol can also be transported by high density lipoprotein (HDL); HDL is believed to be able to remove cholesterol from atheroma within arteries and cholesterol associated with HDL is considered to be beneficial for cardiovascular health. Cholesterol levels are determined by dietary intake, de novo synthesis and secretion by the liver: cholesterol absorption blockers and HMG-CoA reductase inhibitors (statins), which block cholesterol synthesis, are used clinically to reduce cholesterol levels.
A study led by researchers at the University of Cincinnati has now identified a new potential target for the control of cholesterol. The study, carried out in mice, found that circulation of cholesterol is regulated in the brain by the ‘hunger hormone’, ghrelin, which inhibits the melanocortin 4 receptor (MC4R) in the hypothalamus and is important for the regulation of food intake and energy expenditure. Increased levels of ghrelin were associated with increased levels of circulating HDL cholesterol, which the authors attribute to a reduction in the uptake of cholesterol by the liver. Genetically deleting or chemically blocking MCR4 in the CNS also led to increased levels of HDL cholesterol, suggesting that MCR4 is key to central control of cholesterol.
More studies are need to determine whether the effects observed in mice can be applied to humans but the finding that a neural circuit may be directly involved in the control of cholesterol metabolism by the liver could provide a target for new treatments to control cholesterol.
The immunomodulator, FTY720 (fingolimod) is currently undergoing phase III clinical trials for the treatment of relapsing-remitting multiple sclerosis. FTY720 is a prodrug that, once phosphorylated to FTY720-P, is believed to act primarily by targeting sphingosine-1-phosphate (S1P) receptors on lymphocytes and endothelial cells. This leads to retention of lymphocytes in lymph nodes that, in turn, prevents attacks on myelin sheaths.
Although FTY720-P is a potent agonist of several S1P receptors, its beneficial effects in multiple sclerosis are believed to be mediated primarily through the S1P1 receptor. Because specific knockout of the S1P1 receptor on haematopoietic cells in mice and treatment with FTY720 show similar effects on lymphocyte recirculation, the efficacy of FTY720-P has been attributed to ‘functional antagonism’ leading to complete internalisation and desensitisation of receptors. However, writing in the journal Nature Chemical Biology, scientists at Novartis now provide evidence that, despite internalisation, signalling by S1P1 receptors bound to FTY720-P persists for hours. Although calcium signalling – which depends on cell surface localisation of the receptor – was inhibited by treatment with FTY720, other signalling pathways remained activated. In both stably transfected and primary cell lines, persistent activation of S1P1 receptors by FTY720 led to prolonged inhibition of adenylate cyclase and increased ERK phosphorylation. Similar effects were not observed with the endogenous agonist, S1P, and by exploring analogues of FTY-720, the length of the aliphatic side chain was found to be crucially important for persistent signalling and receptor internalisation.
Shortening the lipophilic side chain by one methylene group decreased the effect and shortening by two methylene groups abolished the effect completely, despite all three compounds having similar intrinsic potencies. The ability of the S1P1 antagonist, WN146 – which does not itself induce lymphocyte sequestration – to inhibit prolonged S1P1 signalling caused by treatment with FTY720-P suggests that direct agonism rather than functional antagonism may be the predominant mechanism of action of FTY720-P.