Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, USA.
School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, MN, USA.
Mol Metab. 2018 Feb;8:51-64. doi: 10.1016/j.molmet.2017.12.002. Epub 2017 Dec 30.
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 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.
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.
鉴定血浆 adropin 浓度的决定因素，这是一种从与代谢控制和血管功能相关的能量平衡相关（ENHO）基因翻译而来的分泌肽。
在人类禁食一夜后获得的血浆中，评估了血浆 adropin 浓度与人口统计学（性别、年龄、BMI）和循环脂质和葡萄糖代谢生物标志物之间的关联。然后在体外培养的人类细胞和动物模型中评估 adropin 表达的调节。
在男性（n=349）中，血浆 adropin 浓度与致动脉粥样硬化的 LDL-胆固醇（LDL-C）水平呈负相关，但在女性（n=401）中则不然。对雄性小鼠肝脏 Enho 表达的分析表明受生物钟控制。表达具有节律性，在黑暗中最大食物摄入量时达到峰值，与 RORα/γ的转录激活相关。在光相的最低点与休息阶段和 Rev-erb 的抑制相关。非人类灵长类动物（恒河猴）的血浆 adropin 浓度也显示出与喂食时间（07:00 h、15:00 h）一致的峰值。ROR 反向激动剂 SR1001 和 7-氧化固醇 7-β-羟固醇和 7-酮胆固醇，或 Rev-erb 激动剂 SR9009，可抑制体外培养的人 HepG2 细胞中的 ENHO 表达。高胆固醇饮食可抑制小鼠肝脏中 adropin 转录的表达。然而，adropin 的过度表达并不能防止高胆固醇饮食和/或 LDL 受体突变引起的高胆固醇血症。
在人类中，血浆 adropin 浓度与 LDL-C 之间的关联表明与肝脏脂质代谢有关。小鼠研究表明，adropin 与胆固醇代谢之间的关系是单向的，主要涉及胆固醇和 7-氧化固醇对 adropin 表达的抑制。RORα/γ配体结合域对脂肪酸、胆固醇和氧化固醇的感应表明，adropin 表达与细胞脂质代谢之间可能存在功能联系。此外，核受体 RORα/γ和 Rev-erb 可能将 adropin 合成与碳水化合物和脂质代谢的昼夜节律联系起来。
