Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging.
Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging.
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DOI：
10.1530/joe-11-0406
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Kamat A
中科院分区：
文献类型：
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作者：
Ghosh PM;Shu ZJ;Zhu B;Lu Z;Ikeno Y;Barnes JL;Yeh CK;Zhang BX;Katz MS;Kamat A
肝脏中过多的脂肪堆积（肝脂肪变性）易导致肝脏功能和结构损伤以及整体代谢风险。先前的研究指出了人类和啮齿类动物肝脏脂肪变性与年龄之间的关系。然而，导致与年龄相关的肝脏脂肪积累的机制仍不清楚。本小组早期的研究表明，随着年龄的增长，大鼠肝脏中β-肾上腺素能受体（β-AR）水平和β-AR刺激的腺苷酸环化酶活性增加。在这里，我们研究了年龄相关的β-AR信号的增加是否在增加肝脏脂质积累中起作用。我们证明了衰老过程中肝脏脂质含量的增加，以及肝脂肪含量与β-AR激动剂异丙肾上腺素刺激大鼠肝脏腺苷酸环化酶活性之间的显著相关性。异丙肾上腺素给药使小鼠肝脏脂质积累增加。此外，在体外，幼龄啮齿动物肝细胞中β1-和β2-AR亚型的过表达增加了细胞脂质含量，而受体亚型特异性抑制剂抑制β- ar可降低衰老动物肝细胞中的脂质水平。β-AR非选择性阻滞剂心得安可以阻止异丙肾上腺素在体内引起的肝脂质积累，这表明这类药物在肝脂肪变性中具有新的治疗作用。抑制脂肪组织脂解的阿匹莫司没有改变异丙肾上腺素介导的肝脏脂肪堆积；因此，β-AR反应性肝脂质积累似乎并不主要与脂肪分解改变有关。这些发现提示，衰老过程中肝脏β-AR信号的增强可能会增加肝脏脂质积累，并提示β-肾上腺素能阻滞剂可能在预防或延缓肝脂肪变性的发展中起作用。
Excessive fat accumulation in liver (hepatic steatosis) predisposes to hepatic functional and structural impairment and overall metabolic risk. Previous studies noted an association between hepatic steatosis and age in humans and rodents. However, the mechanisms leading to age-associated hepatic fat accumulation remain unknown. Earlier work from our group showed that β-adrenergic receptor (β-AR) levels and β-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Here we investigated whether age-associated increases in β-AR signaling play a role in augmenting hepatic lipid accumulation. We demonstrate an increase in hepatic lipid content during senescence and a significant correlation between hepatic fat content and stimulation of adenylyl cyclase activity by the β-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of β1- and β2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of β-ARs by receptor subtype-specific inhibitors reduced lipid levels in hepatocytes from senescent animals. Isoproterenol-induced hepatic lipid accumulation in vivo was prevented by the β-AR nonselective blocker propranolol, suggesting a novel therapeutic effect of this class of drugs in hepatic steatosis. Acipimox, which inhibits adipose tissue lipolysis, did not alter isoproterenol-mediated hepatic fat accumulation; thus β-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic β-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for β-adrenergic blockers in preventing or retarding the development of hepatic steatosis.