Abstract:
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.
摘要:
经典遗传性血色素沉着病(HH)是一种常染色体隐性铁过载疾病,由HFE基因的功能丧失突变引起。HH患者表现出过多的肝铁积累,使这些患者容易患上肝病,包括患肝癌的风险。慢性铁超负荷也会带来代谢紊乱如肥胖的风险,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),在HH小鼠模型中改变铁代谢,同时还降低体重和葡萄糖耐量(全球HFE敲除,HFEKO)和饮食诱导的肥胖和葡萄糖耐受不良。全身HFEKO和WT对照小鼠饲喂高脂饮食8周。将小鼠细分为利拉鲁肽和媒介物治疗组,并接受每天一次的各自治疗的每日皮下施用,持续18周。利拉鲁肽改善葡萄糖耐量,在HH小鼠模型中,肝脏脂质标志物和体重减轻,HFEKO鼠标,类似于WT控制。重要的是,我们的数据显示利拉鲁肽改变了HFEKO小鼠的铁代谢,导致HFEKO小鼠循环和储存的铁水平降低。这些观察结果突出了GLP1RA除了在HH患者中减轻体重和改善葡萄糖调节之外还可用于减少铁超负荷的潜力。