List of primer sets for qPCR.

Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain–liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain–liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.

肝脏脂质代谢受肝脏自主神经系统调控，其中交感神经支配的相关机制已得到广泛研究，而副交感传出神经支配虽具有重要潜力，却尚未得到充分阐明。本研究以暴露于致肥胖环境的小鼠为模型，探究脑-肝通讯紊乱对肝脏脂质代谢的影响。研究发现，部分肝细胞与胆管上皮细胞接受源自迷走神经背运动核的副交感神经末梢支配。通过敲除支配肝脏的副交感胆碱能神经元以切断脑-肝轴，可阻断肝脂肪变性的发生，并促进腹股沟白色脂肪组织（inguinal white adipose tissue，ingWAT）的褐变进程。缺失肝脏支配的胆碱能神经元可上调肝脏Cyp7b1的表达水平，并升高空腹血清胆汁酸浓度。进一步实验表明，在ingWAT中敲低G蛋白偶联胆汁酸受体1基因（G protein-coupled bile acid receptor 1 gene），可逆转缺失肝脏支配胆碱能神经元带来的有益效应，使肝脂肪变性复现。敲除肝脏支配胆碱能神经元会对小鼠体重产生小幅但显著的影响，同时伴随能量消耗的增加。综上，本研究数据提示，靶向肝脏的副交感胆碱能神经支配，或可作为改善肥胖与糖尿病患者肝脏脂质代谢的潜在治疗手段。