Liver sympathetic denervation reverses obesity-induced hepatic steatosis
Liver sympathetic denervation reverses obesity-induced hepatic steatosis
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DOI：
10.1113/jp277994
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发表时间：
2019-07-26
影响因子：
5.5
通讯作者：
Young, Colin N.
中科院分区：
文献类型：
--
作者：
Hurr, Chansol;Simonyan, Hayk;Young, Colin N.
关键点非酒精性脂肪性肝病，其特征部分是肝脏甘油三酯升高（即肝脂肪变性），是一个日益严重的健康问题。在这项研究中，我们发现肝脂肪变性与强烈的肝交感神经过度活跃有关。去除肝交感神经可减少肥胖引起的肝脏脂肪变性。肥胖时肝脏交感神经支配调节肝脏脂质获得途径。非酒精性脂肪性肝病（NAFLD）影响三分之一的美国人，是II型糖尿病，胰岛素抵抗和肝癌的重要危险因素。NAFLD的部分特征是过度的肝脏甘油三酯积累（即肝脏脂肪变性），其发病率正在增加-与日益增长的肥胖流行一致。自主神经系统在NAFLD中的作用尚不清楚。在这里，我们表明，慢性肝交感神经过度活跃介导肝脂肪变性。在高脂饮食和正常食物喂养的雄性C57 BL/6 J小鼠中获得肝交感神经活动的直接多单位记录。为了减少肝交感神经活性，我们采用了两种方法，包括交感神经的药物消融和基于苯酚的肝交感神经去神经。饮食诱导的NAFLD与肝交感神经的放电率几乎加倍相关，这主要是由于传出神经交通的增加。此外，通过药理学或基于苯酚的肝交感神经去除，可有效降低已建立的高脂肪饮食诱导的肝脂肪变性，与体重、热量摄入或肥胖的变化无关。肝交感神经消融还与肝脏甘油三酯蓄积途径（包括游离脂肪酸摄取和新生脂肪生成）的改善相关。这些发现强调了肝交感神经流出和肝脂肪变性之间未被认识到的致病联系，并表明肝交感神经的操纵可能是NAFLD的一种新的治疗策略。
Key pointsNon-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity. Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD.