Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

中文翻译：

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cAMP 和磷酸二酯酶信号在肝脏健康和疾病中的作用。

肝病是世界范围内的一个重大健康问题，每年约有 200 万人死亡。非酒精性脂肪肝病（NAFLD）和酒精性肝病（ALD）是慢性肝病的主要原因。从病理学角度来看，NAFLD 和 ALD 具有相似的肝脏疾病模式，从单纯性脂肪变性到脂肪性肝炎、纤维化和肝硬化。鉴于目前 FDA 还没有批准针对 NAFLD 或 ALD 的治疗方法，因此确定新的药理学靶点变得越来越重要。由于肝脏疾病的演变是一个多因素的过程，涉及实质和非实质肝细胞的多种机制有助于肝脏病理的发生和进展。此外，某些保护性分子途径在肝损伤期间受到抑制，包括信号传导途径，例如环磷酸腺苷（cAMP）途径。cAMP 是一种关键的第二信使分子，通过影响基因/蛋白质的表达和功能来调节各种细胞功能，包括脂质代谢、炎症、细胞分化和损伤。这篇综述阐述了目前对 cAMP 代谢和随后的 cAMP 信号通路在肝脏健康和疾病中的作用的理解。cAMP 途径极其精密和复杂，其特定的细胞功能由许多因素决定，例如磷酸二酯酶 (PDE) 的丰度、定位和降解。此外，由于其两种效应分子的作用不同但又不同，cAMP 通路广泛针对肝损伤，根据肝脏状况将其作用从生理作用转变为治疗作用。本综述还研究了 cAMP 依赖性通路在 NAFLD、ALD 和其他肝脏疾病中的行为，并重点关注 PDE 抑制作为这些疾病的绝佳治疗靶点。