目的:肝脏极低密度脂蛋白(VLDL)-甘油三酯(TG)分泌升高导致与肥胖相关的动脉粥样硬化血脂异常,糖尿病和代谢综合征。许多肥胖和糖尿病模型的特征是中枢神经系统(CNS)神经肽Y(NPY)增加;事实上,一个单一的侧脑室(icv)给药NPY在瘦禁食大鼠升高肝VLDL-TG分泌,这样做,在很大程度上,通过CNSNPYY1受体的信号传导。因此,我们的总体假设是,CNSNPY作用的升高通过激活调节肝脏脂质代谢的中枢回路而导致血脂异常.
方法:通过将热量摄入与瘦对照组的热量摄入以及对体重的影响进行配对喂养,血浆TG,将TG和磷脂(PL)的肝脏含量与随意喂养的ZF大鼠进行比较。此外,用icvNPY或NPYY1受体激动剂治疗具有完整或破坏的肝交感神经支配的瘦肉4小时禁食大鼠,以确定NPY促进VLDL颗粒成熟和分泌的新肝脏机制。
结果:操纵肥胖ZF大鼠的血浆TG水平,通过配对喂养对肝脏TG含量没有影响;然而,肝脏PL含量显著降低,且与血浆TG水平密切相关.用icvNPY或选择性NPYY1受体激动剂治疗精瘦禁食大鼠的关键肝调节蛋白,硬脂酰辅酶A去饱和酶-1(SCD-1),ADP-核糖基化因子-1(ARF-1),和lipin-1,已知参与将肝脏PL重塑为TG以促进VLDL成熟和分泌。最后,我们表明,中枢神经系统NPY对关键脂调节蛋白的影响通过肝交感神经支配减弱。
结论:这些数据支持一个模型,其中CNSNPY调节肝PL重塑和VLDL成熟的介质以刺激VLDL-TG分泌,该分泌依赖于Y1受体和肝脏的交感神经信号。
OBJECTIVE: Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism.
METHODS: Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion.
RESULTS: Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation.
CONCLUSIONS: These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is dependent on the Y1 receptor and sympathetic signaling to the liver.