Abstract
Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an important regulator of cholesterol in rodents. Inhibiting the brain's melanocortin system by pharmacological, genetic or endocrine mechanisms increased circulating HDL cholesterol by reducing its uptake by the liver independent of food intake or body weight. Our data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver.
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Acknowledgements
This work was supported by US National Institute of Health grants NIDDK56863 (S.C.W. and M.H.T.), 5R01DK077975 (M.H.T.), R01 DK076907 (D.Y.H.) and HL67093 (W.S.D.). S.M.H. is the recipient of a Scientist Development Award from the American Heart Association (#0635079N). S.M.H. is a recipient of a Basic Science Award (1-10-BS-72) from the American Diabetes Association.
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D.P.-T., S.M.H., J.B., R.N. and P.T.P. designed and performed most of the experiments and wrote the manuscript. J.L.T. performed experiments, J.T.P. synthesized receptor ligands and A.A.B., S.C.B. and M.W.S. generated mouse models. N.G. carried out FPLC analyses. W.S.D. performed lipoprotein electrophoresis, E.G. and H.W.-P. carried out in vivo experiments, gene expression, inmunoblots and inmunoassays, M.A. performed surgical procedures and S.C.W. interpreted data and co-wrote the manuscript. R.D.D., D.Y.H. and M.H.T. conceptualized, analyzed and interpreted all studies and co-wrote the manuscript.
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R.D.D. and M.H.T. are scientific advisors for and shareholders of Marcadia Biotech and Ambrx Inc.
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Perez-Tilve, D., Hofmann, S., Basford, J. et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci 13, 877–882 (2010). https://doi.org/10.1038/nn.2569
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DOI: https://doi.org/10.1038/nn.2569
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