Adropin: an endocrine link between the biological clock and cholesterol homeostasis.

Authors: GHOSHAL, SARBANI - St Louis University; STEVENS, JOSEPH - St Louis University; BILLON, CYRIELLE - St Louis University; GIRADET, CLEMENCE - St Louis University; SITUALA, SADICHHA - St Louis University; LEON, ARTHUR - University Of Minneapolis; RAO, D.C. - Washington University School Of Medicine; SKINNER, JAMES - Indiana University; RANKINEN, TUOMO - Louisiana State University; BOUCHARD, CLAUDE - Louisiana State University; NUNEZ, MARINELLE - University Of California, Davis; STANHOPE, KIMBER - University Of California, Davis; HOWATT, DEBORAH - University Of Kentucky; DAUGHERTY, ALAN - University Of Kentucky; ZHANG, JINSONG - St Louis University; SCHUELKE, MATTHEW - St Louis University; WEISS, EDWARD - St Louis University; BURRIS, THOMAS - St Louis University; HAVEL, PETER - University Of California, Davis; BUTLER, ANDREW - St Louis University; Bennett, Brian; SETHUPATHY, PRAVNEEN - Cornell University

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/2/2017
Publication Date: 12/30/2017
Citation: Ghoshal, S., Stevens, J.R., Billon, C., Giradet, C., Situala, S., Leon, A.S., Rao, D., Skinner, J.S., Rankinen, T., Bouchard, C., Nunez, M.V., Stanhope, K.L., Howatt, D.A., Daugherty, A., Zhang, J., Schuelke, M., Weiss, E.P., Burris, T.P., Havel, P.J., Butler, A.A., Bennett, B.J., Sethupathy, P. 2017. Adropin: an endocrine link between the biological clock and cholesterol homeostasis. Molecular Metabolism. 8:51-64. https://doi.org/10.1016/j.molmet.2017.12.002.
DOI: https://doi.org/10.1016/j.molmet.2017.12.002

Interpretive Summary: Secreted peptides are involved in signaling metabolic status at the organismal and cellular levels to maintain cardiovascular and metabolic homeostasis. Studies in male C57BL/6J (B6) mice suggest the secreted peptide adropin provides such a signal of metabolic condition. Adropin is a product of the Energy Homeostasis Association (ENHO) gene, comprised of two exons on human chromosome 9p13.3. Adropin alters whole body glucose and lipid metabolism when administered to mice, rats, and also activates signaling pathways in mammalian cell lines. The Enho transcript is however widely expressed, with high levels of expression in the nervous system relative to other tissues in mice. Analysis of mice that are adropin-deficient, over express adropin or are administered pharmacological doses of synthetic peptide suggest adropin suppresses fat oxidation and enhances oxidative glucose disposal and glucose tolerance. Studies investigating plasma adropin concentrations in humans and nonhuman primates have observed associations with diet, with indices of insulin resistance, and with risk for cardiovascular disease. However, determinants of plasma adropin concentration in humans are still poorly defined. Here we report that plasma adropin concentrations are inversely related to plasma levels of low density lipoprotein cholesterol (LDL-C) in males, but not in females. We also report that the biological clock may be plausible focal point linking Enho transcription with nutrient intake and cellular metabolic condition.

Technical 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 RORA/G. 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 (0700h, 1500h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-beta-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 fat 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 predominantly unidirectional, and involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. The nuclear receptors RORA/G and Rev-erb may also couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism. Furthermore, sensing of fatty acids, cholesterol and oxysterols by the RORA/G ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism.