Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis.
Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis.
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DOI：
10.1002/path.4760
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发表时间：
2016-09
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影响因子：
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通讯作者：
Gobejishvili L
中科院分区：
文献类型：
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作者：
Avila DV;Barker DF;Zhang J;McClain CJ;Barve S;Gobejishvili L
酒精引起的肝脂肪变性是进行性肝病的重要危险因素。环磷酸腺苷 (cAMP) 信号传导已被证明可以显着调节脂质代谢；然而，cAMP 稳态改变在酒精介导的肝脂肪变性中的作用从未被研究过。我们之前的工作表明，特异性水解并降低 cAMP 水平的肝磷酸二酯酶 4 (Pde4) 表达增加，在肝脏炎症/损伤的发展中发挥致病作用。本研究的目的是探讨 PDE4 在酒精诱导的肝脂肪变性中的作用。 C57BL/6 野生型和 Pde4b 敲除 (Pde4b−/−) 小鼠采用配对喂养对照或乙醇液体饮食。一组野生型小鼠在饮酒期间接受了咯利普兰（一种 PDE4 特异性抑制剂）。我们首次证明 PDE4 酶表达的早期增加和由此导致的肝脏 cAMP 水平的降低与肉碱棕榈酰转移酶 1A (Cpt1a) 表达的显着降低相关。值得注意的是，与 AF 野生型小鼠相比，酒精喂养 (AF) Pde4b−/− 小鼠和用咯利普兰治疗的 AF 野生型小鼠的肝游离脂肪酸含量显着降低。重要的是，在酒精喂养的小鼠中，PDE4 抑制可通过 Pparα/Sirt1/Pgc1α 途径阻止肝脏 Cpt1a 表达的减少。这些结果表明，酒精诱导的肝脏 Pde4（特别是 Pde4b）表达增加以及 cAMP 信号传导受损使肝脏易于受损的脂肪酸氧化和脂肪变性的发展。此外，这些数据还表明肝脏PDE4可能是治疗酒精诱导的肝脂肪变性的临床相关治疗靶点。
Alcohol induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signalling has been shown to significantly regulate lipid metabolism; however, the role of altered cAMP homeostasis in alcohol mediated hepatic steatosis has never been studied. Our previous work demonstrated that increased expression of hepatic phosphodiesterase 4 (Pde4), which specifically hydrolyses and decreases cAMP levels, plays a pathogenic role in the development of liver inflammation/injury. The aim of this study was to examine the role of PDE4 in alcohol-induced hepatic steatosis. C57BL/6 wild type and Pde4b knockout (Pde4b−/−) mice were pair-fed control or ethanol liquid diets. One group of wild type mice received rolipram, a PDE4 specific inhibitor, during alcohol feeding. We demonstrate for the first time that an early increase in PDE4 enzyme expression and a resultant decrease in hepatic cAMP levels are associated with the significant reduction in carnitine palmitoyltransferase 1A (Cpt1a) expression. Notably, alcohol fed (AF) Pde4b−/− mice and AF wild type mice treated with Rolipram had significantly lower hepatic free fatty acid content compared to AF wild type mice. Importantly, PDE4 inhibition in alcohol fed mice prevented the decrease in hepatic Cpt1a expression via the Pparα/Sirt1/Pgc1α pathway. These results demonstrate that the alcohol- induced increase in hepatic Pde4, specifically Pde4b expression, and compromised cAMP signalling predisposes the liver to impaired fatty acid oxidation and the development of steatosis. Moreover, these data also suggest that hepatic PDE4 may be a clinically relevant therapeutic target for the treatment of alcohol induced hepatic steatosis.