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 L. 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 journalArticlepeer-review

23 Scopus citations

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)
Pages (from-to)51-64
Number of pages14
JournalMolecular Metabolism
Volume8
DOIs
StatePublished - Feb 2018

Bibliographical note

Funding Information:
AAB acknowledges support from the Lottie Caroline Hardy Charitable Trust. The CREG study was supported by K01-DK-080886 and DK-56341 (Nutrition and Obesity Research Center) and UL1-RR-024992 (Clinical Translational Science Award). Dr. Havel's and Dr. Stanhope's laboratory received funding from R01-HL-075675, R01-HL-091333. R01-HL-107256, R01-HL-121324, 1R01-HL-121324-02S1 and a multi-campus Award from the University of California, Office of the President. The HERITAGE Family Study was funded by HL-45670, HL-47323, HL-47317, HL-47327, and HL-47321 (CB, TR, DR, AL, JSS). C. Bouchard is also partially funded by the John W. Barton Sr. Chair in Genetics and Nutrition. AC, BB, DP and PS acknowledge support from 5R01HL128572 (BJB), P30DK056350 (BJB, DP), R01DK105965 (PS), a pilot grant from the Nutrition Research Institute (BJB, PS), and an NSF Graduate Research Fellowship Program DGE-1144081 (ARC). TB acknowledges the support of 5R01MH092769 and 5R01MH093429.

Funding Information:
AAB acknowledges support from the Lottie Caroline Hardy Charitable Trust . The CREG study was supported by K01-DK-080886 and DK-56341 ( Nutrition and Obesity Research Center ) and UL1-RR-024992 ( Clinical Translational Science Award ). Dr. Havel's and Dr. Stanhope's laboratory received funding from R01-HL-075675, R01-HL-091333. R01-HL-107256, R01-HL-121324, 1R01-HL-121324-02S1 and a multi-campus Award from the University of California, Office of the President. The HERITAGE Family Study was funded by HL-45670, HL-47323, HL-47317, HL-47327, and HL-47321 (CB, TR, DR, AL, JSS). C. Bouchard is also partially funded by the John W. Barton Sr. Chair in Genetics and Nutrition. AC, BB, DP and PS acknowledge support from 5R01HL128572 (BJB), P30DK056350 (BJB, DP), R01DK105965 (PS), a pilot grant from the Nutrition Research Institute (BJB, PS), and an NSF Graduate Research Fellowship Program DGE-1144081 (ARC). TB acknowledges the support of 5R01MH092769 and 5R01MH093429.

Keywords

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

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