Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from hepatic steatosis (excessive accumulation of triglycerides [TG]) to nonalcoholic steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The molecular pathogenesis of steatosis and progression to more severe NAFLD remains unclear. Obesity and aging, two principal risk factors for NAFLD, are associated with a hyperadrenergic state. β-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of β₂-adrenergic receptors (β₂-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of β₂-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective β₂-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying β₂-AR mediated steatosis by investigating changes in hepatic expression and cellular localization of enzymes, transcription factors and coactivators involved in processes of lipid accrual and disposition-and also functional aspects thereof-in livers of formoterol treated animals. Our results suggest that β₂-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete β-oxidation of fatty acids with accumulation of potentially toxic long-chain acylcarnitine intermediates, and reduced TG secretion-all previously invoked as contributors to fatty liver disease. Experiments are ongoing to determine whether sustained activation of hepatic β₂-AR signaling by formoterol might be utilized to model fatty liver changes occurring in hyperadrenergic states of obesity and aging, and thereby identify novel molecular targets for the prevention or treatment of NAFLD.

中文翻译：

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β2-肾上腺素能受体激动剂诱导小鼠肝脂肪变性：在高肾上腺素能状态下模拟非酒精性脂肪肝


非酒精性脂肪肝病 (NAFLD) 是一系列疾病，从肝脂肪变性（甘油三酯 [TG] 过度积累）到非酒精性脂肪性肝炎，可进展为肝硬化和肝细胞癌。脂肪变性和进展为更严重的 NAFLD 的分子发病机制仍不清楚。肥胖和衰老是 NAFLD 的两个主要危险因素，与肾上腺素能亢进状态有关。在肥胖和衰老的动物模型中，肝脏中的 β-肾上腺素反应性增加，并且两者都与_β2-肾上腺素受体 ( _β2 -AR) 的肝脏表达增加有关。我们之前表明，在衰老啮齿动物中，肝脏 β ₂ -AR 水平升高的细胞内信号传导可能导致肝脏脂肪变性。在这项研究中，我们证明给小鼠注射福莫特罗（一种高选择性 β ₂ -AR 激动剂）会急剧导致肝脏 TG 积累。此外，我们试图通过研究肝脏中参与脂质累积和处置过程及其功能方面的酶、转录因子和共激活剂的肝表达和细胞定位的变化来定义β ₂ -AR介导的脂肪变性的肝内机制福莫特罗治疗的动物。我们的结果表明，福莫特罗激活 β ₂ -AR 会导致肝脏 TG 合成和从头脂肪生成增加，脂肪酸 β-氧化增加但不完全，并积累潜在有毒的长链酰基肉碱中间体，并减少 TG 分泌 - 所有这些都先前提到过作为脂肪肝疾病的促成因素。 实验正在进行中，以确定福莫特罗对肝脏 β ₂ -AR 信号传导的持续激活是否可用于模拟肥胖和衰老的肾上腺素能亢进状态下发生的脂肪肝变化，从而确定预防或治疗 NAFLD 的新分子靶点。