Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages.

Abstract

BACKGROUND:

The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte-stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation.

METHODS:

Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E-deficient mice.

RESULTS:

Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow-derived macrophages, we observed that α-melanocyte-stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E-deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability.

CONCLUSIONS:

Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse cholesterol transport.

• Authors: Petteri Rinne, Martina Rami, Salla Nuutinen, Donato Santovito, Emiel P C van der Vorst, Raquel Guillamat-Prats, Leo-Pekka Lyytikäinen, Emma Raitoharju, Niku Oksala, Larisa Ring, Minying Cai, Victor J Hruby, Terho Lehtimäki, Christian Weber, Sabine Steffens
• Journal: Circulation (Circulation) Vol. 136 Issue 1 Pg. 83-97 (Jul 04 2017) ISSN: 1524-4539 [Electronic] United States
• PMID: 28450348 (Publication Type: Journal Article)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• Receptor, Melanocortin, Type 1
• alpha-MSH
• Cholesterol

Topics

• Animals
• Biological Transport (drug effects, physiology)
• Cholesterol (metabolism)
• Female
• Foam Cells (drug effects, metabolism)
• HEK293 Cells
• Humans
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Random Allocation
• Receptor, Melanocortin, Type 1 (agonists, metabolism)
• Signal Transduction (drug effects, physiology)
• alpha-MSH (metabolism, pharmacology)