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Publication
Adropin: An endocrine link between the biological clock and cholesterol
homeostasis.
Authors Ghoshal S, Stevens JR, Billon C, Girardet C, Sitaula S, Leon AS, Rao DC, Skinner
JS, Rankinen T, Bouchard C, Nuñez MV, Stanhope KL, Howatt DA, Daugherty A, Zhang
J, Schuelke M, Weiss EP, Coffey AR, Bennett BJ, Sethupathy P, Burris TP, Havel
PJ, Butler AA
Submitted By Submitted Externally on 11/5/2018
Status Published
Journal Molecular metabolism
Year 2018
Date Published 2/1/2018
Volume : Pages 8 : 51 - 64
PubMed Reference 29331507
Abstract Identify determinants of plasma adropin concentrations, a secreted peptide
translated from the Energy Homeostasis Associated (ENHO) gene linked to
metabolic control and vascular function., 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., 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 RORa/?. 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-ß-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., 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 RORa/?
ligand-binding domain suggests a plausible functional link between adropin
expression and cellular lipid metabolism. Furthermore, the nuclear receptors
RORa/? and Rev-erb may couple adropin synthesis with circadian rhythms in
carbohydrate and lipid metabolism.




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