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From skin pigmentation to cholesterol homeostasis

04.05.2017 -

Melanocortin 1 receptor (MC1-R) is best known for its central role in regulating skin and hair colour. A recent study, led by Professor Sabine Steffens and Dr Petteri Rinne, identified a completely new action for this receptor in macrophage cholesterol transport.


MC1-R is abundantly expressed by melanocytes in the skin where it stimulates melanin production and confers protection against UV radiation. The same receptor was also found to be present in macrophages in human and mouse atherosclerotic plaques. Interestingly, the amount of MC1-R in plaques correlated with transporters that are known to unload excess cholesterol from macrophages, namely ABCA1 and ABCG1. This led to a hypothesis that MC1-R could serve as a protective regulator of macrophage cholesterol transport, which is an atheroprotective mechanism.


By using cultured macrophages and pharmacological tools, it became evident that MC1-R indeed promotes the ability of macrophages to handle cholesterol. Activation of the receptor evokes a dual response: it reduces the uptake of cholesterol in the form of modified lipoproteins such as oxidized LDL and at the same time enhances the removal of intracellular cholesterol trough a process called cholesterol efflux. Conversely, deficiency of MC1-R associates with impaired cholesterol efflux and increased tendency to foam cell formation. 


This finding have therapeutic implications in atherosclerosis, since macrophage cholesterol efflux is an important counter-regulatory mechanism against disturbed cholesterol homeostasis. It alleviates cholesterol burden and inflammation in diseased arteries and helps macrophages to maintain their pro-resolving properties. Ideally, targeting macrophage cholesterol efflux could complement other cholesterol-lowering therapies to control for the residual risk that is often present in medically treated patients with atherosclerotic disease.


The research was published in Circulation:


Petteri Rinne, Martina Rami, Salla Nuutinen, Donato Santovito, Emiel van der Vorst, Raquel Guillamat Prats, Leo-Pekka Lyytikäinen, Emma Raitoharju, Niku Oksala, Larisa Ring, Minying Cai, Victor Hruby, Terho Lehtimäki, Christian Weber & Sabine Steffens. Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages Circulation (2017).