Adropin: An endocrine link between the biological clock and cholesterol homeostasis
OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circula...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985041/ https://www.ncbi.nlm.nih.gov/pubmed/29331507 http://dx.doi.org/10.1016/j.molmet.2017.12.002 |
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author | Ghoshal, Sarbani Stevens, Joseph R. Billon, Cyrielle Girardet, Clemence Sitaula, Sadichha Leon, Arthur S. Rao, D.C. Skinner, James S. Rankinen, Tuomo Bouchard, Claude Nuñez, Marinelle V. Stanhope, Kimber L. Howatt, Deborah A. Daugherty, Alan Zhang, Jinsong Schuelke, Matthew Weiss, Edward P. Coffey, Alisha R. Bennett, Brian J. Sethupathy, Praveen Burris, Thomas P. Havel, Peter J. Butler, Andrew A. |
author_facet | Ghoshal, Sarbani Stevens, Joseph R. Billon, Cyrielle Girardet, Clemence Sitaula, Sadichha Leon, Arthur S. Rao, D.C. Skinner, James S. Rankinen, Tuomo Bouchard, Claude Nuñez, Marinelle V. Stanhope, Kimber L. Howatt, Deborah A. Daugherty, Alan Zhang, Jinsong Schuelke, Matthew Weiss, Edward P. Coffey, Alisha R. Bennett, Brian J. Sethupathy, Praveen Burris, Thomas P. Havel, Peter J. Butler, Andrew A. |
author_sort | Ghoshal, Sarbani |
collection | PubMed |
description | OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. RESULTS: In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. CONCLUSIONS: In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism. |
format | Online Article Text |
id | pubmed-5985041 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-59850412018-06-04 Adropin: An endocrine link between the biological clock and cholesterol homeostasis Ghoshal, Sarbani Stevens, Joseph R. Billon, Cyrielle Girardet, Clemence Sitaula, Sadichha Leon, Arthur S. Rao, D.C. Skinner, James S. Rankinen, Tuomo Bouchard, Claude Nuñez, Marinelle V. Stanhope, Kimber L. Howatt, Deborah A. Daugherty, Alan Zhang, Jinsong Schuelke, Matthew Weiss, Edward P. Coffey, Alisha R. Bennett, Brian J. Sethupathy, Praveen Burris, Thomas P. Havel, Peter J. Butler, Andrew A. Mol Metab Original Article OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. RESULTS: In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. CONCLUSIONS: In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism. Elsevier 2017-12-30 /pmc/articles/PMC5985041/ /pubmed/29331507 http://dx.doi.org/10.1016/j.molmet.2017.12.002 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Ghoshal, Sarbani Stevens, Joseph R. Billon, Cyrielle Girardet, Clemence Sitaula, Sadichha Leon, Arthur S. Rao, D.C. Skinner, James S. Rankinen, Tuomo Bouchard, Claude Nuñez, Marinelle V. Stanhope, Kimber L. Howatt, Deborah A. Daugherty, Alan Zhang, Jinsong Schuelke, Matthew Weiss, Edward P. Coffey, Alisha R. Bennett, Brian J. Sethupathy, Praveen Burris, Thomas P. Havel, Peter J. Butler, Andrew A. Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title | Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title_full | Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title_fullStr | Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title_full_unstemmed | Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title_short | Adropin: An endocrine link between the biological clock and cholesterol homeostasis |
title_sort | adropin: an endocrine link between the biological clock and cholesterol homeostasis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985041/ https://www.ncbi.nlm.nih.gov/pubmed/29331507 http://dx.doi.org/10.1016/j.molmet.2017.12.002 |
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