Role of cAMP and phosphodiesterase signaling in liver health and disease

Abstract

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.

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench

“…These findings are significant because cAMP signaling is very important for the liver and inadequate cAMP levels would compromise normal functioning of the liver. (8) Indeed, the present in vivo and in vitro studies demonstrated that the ethanolmediated decrease in cAMP signaling predisposes hepatocytes to increased ER stress and apoptosis.…”

“…Nevertheless, hepatocytes of patients with AH had much greater immune‐reactivity for all three PDE4s, which implicates PDE4 as a likely source of dysregulated cAMP signaling in livers from patients with AH. These findings are significant because cAMP signaling is very important for the liver and inadequate cAMP levels would compromise normal functioning of the liver . Indeed, the present in vivo and in vitro studies demonstrated that the ethanol‐mediated decrease in cAMP signaling predisposes hepatocytes to increased ER stress and apoptosis.…”

“…cAMP regulates numerous pathways in different cell types and organs including inflammation and cell survival. The significance of cAMP signaling in liver health and disease is well established . cAMP levels are controlled through its synthesis by adenylyl cyclase, and its degradation by a large family of phosphodiesterases (PDEs).…”

“…The significance of cAMP signaling in liver health and disease is well established. (8) cAMP levels are controlled through its synthesis by adenylyl cyclase, and its degradation by a large family of phosphodiesterases (PDEs). cAMP exerts its effect through effector proteins such as protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), cyclic nucleotide activated ion channels, and popeye domain containing proteins.…”

Epinephrine responsiveness is reduced in livers from trained mice

“…Epinephrine increases hepatic glycogenolysis and HGP in a cAMP-PKA-dependent pathway (Bousquet-Mélou, Galitzky, Moreno, Berlan, & Lafontan, 1995;Kolnes et al, 2015;Wasserman & Cherrington, 1991). Phosphodiesterase 3B and 4B (PDE3B, PDE4B) are the primary enzymes responsible for the degradation of cAMP in the liver (Avila, Barker, Zhang, McClain, & Barve, 2016;Berger et al, 2009;Omori & Kotera, 2007;Wahlang, McClain, Barve, & Gobejishvili, 2018). Therefore, in order to determine if epinephrine responsiveness was associated with changes in phosphodiesterase expression, we measured Pde3b and Pde4b gene expression in the liver.…”