Adropin: An endocrine link between the biological clock and cholesterol homeostasis

Sarbani Ghoshal, Joseph R. Stevens, Cyrielle Billon, Clemence Girardet, Sadichha Sitaula, Arthur S. Leon, D. C. Rao, James S. Skinner, Tuomo Rankinen, Claude Bouchard, Marinelle V. Nuñez, Kimber Stanhope, Deborah A. Howatt, Alan Daugherty, Jinsong Zhang, Matthew Schuelke, Edward P. Weiss, Alisha R. Coffey, Brian J. Bennett, Praveen SethupathyThomas P. Burris, Peter J Havel, Andrew A. Butler

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Biological Clocks
Homeostasis
Cholesterol
Lipid Metabolism
Sterols
LDL Cholesterol
Liver
Diet
LDL Receptors
Hep G2 Cells
Carbohydrate Metabolism
Cytoplasmic and Nuclear Receptors
Circadian Rhythm
Hypercholesterolemia
Macaca mulatta
Computer Simulation
Primates
Transcriptional Activation
Blood Vessels
Cultured Cells

Keywords

  • Adropin
  • Cardiovascular disease
  • Cholesterol
  • LDL
  • Obesity
  • Sex

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Ghoshal, S., Stevens, J. R., Billon, C., Girardet, C., Sitaula, S., Leon, A. S., ... Butler, A. A. (Accepted/In press). Adropin: An endocrine link between the biological clock and cholesterol homeostasis. Molecular Metabolism. https://doi.org/10.1016/j.molmet.2017.12.002

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; 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.

In: Molecular Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Ghoshal, S, Stevens, JR, Billon, C, Girardet, C, Sitaula, S, Leon, AS, Rao, DC, Skinner, JS, Rankinen, T, Bouchard, C, Nuñez, MV, Stanhope, K, Howatt, DA, Daugherty, A, Zhang, J, Schuelke, M, Weiss, EP, Coffey, AR, Bennett, BJ, Sethupathy, P, Burris, TP, Havel, PJ & Butler, AA 2018, 'Adropin: An endocrine link between the biological clock and cholesterol homeostasis', Molecular Metabolism. https://doi.org/10.1016/j.molmet.2017.12.002
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 ; 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. In: Molecular Metabolism. 2018.
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AU - Stevens, Joseph R.

AU - Billon, Cyrielle

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AU - Sitaula, Sadichha

AU - Leon, Arthur S.

AU - Rao, D. C.

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AU - Coffey, Alisha R.

AU - Bennett, Brian J.

AU - Sethupathy, Praveen

AU - Burris, Thomas P.

AU - Havel, Peter J

AU - Butler, Andrew A.

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N2 - 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.

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