Nadejda Bozadjieva-Kramer, Jae Hoon Shin, Neil B Blok, Chesta Jain, Nupur K Das, Joseph Polex-Wolf, Lotte Bjerre Knudsen, Yatrik M Shah, Randy J Seeley
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引用次数: 0
摘要
典型遗传性血色病(HH)是一种常染色体隐性遗传的铁负荷过重疾病,由 HFE 基因的功能缺失突变引起。HH 患者表现为肝脏铁过度积聚,易患肝病,包括肝癌。长期铁超载还可能导致代谢紊乱,如肥胖、2 型糖尿病和胰岛素抵抗。我们假设利拉鲁肽、GLP1 受体激动剂(GLP1RA)能改变铁代谢,同时还能减轻 HH(全基因 HFE 基因敲除,HFE KO)小鼠模型的体重和葡萄糖耐量,以及饮食诱导的肥胖和葡萄糖不耐受。对全身 HFE KO 和 WT 对照小鼠喂食高脂饮食 8 周。小鼠被细分为利拉鲁肽治疗组和药物治疗组,每天皮下注射一次相应的治疗药物,持续18周。利拉鲁肽改善了HH小鼠模型(HFE KO小鼠)的葡萄糖耐量、肝脏脂质指标并减轻了体重,与WT对照组相似。重要的是,我们的数据显示,利拉鲁肽改变了 HFE KO 小鼠体内的铁代谢,导致 HFE KO 小鼠体内循环和储存的铁水平下降。这些观察结果突出表明,除了减轻体重和改善 HH 患者的血糖调节外,GLP1RA 还有可能用于减轻铁超载。
Liraglutide Impacts Iron Homeostasis in a Murine Model of Hereditary Hemochromatosis.
Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.
期刊介绍:
The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.