Cited by 168Phosphodiesterase function and regulationLiver Disease Diagnosis and TreatmentLiver physiology and pathology

Role of cAMP and phosphodiesterase signaling in liver health and disease

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Wahlang, Banrida, McClain, Craig, Barve, Shirish, Gobejishvili, Leila·2018·Cellular Signalling

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.

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Crossref · 10.1016/j.cellsig.2018.06.005

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  • De-differentiation of human macrophages into monocyte-like cells has been shown to be induced by bacterial toxins that elevate cAMP.

    “The de-differentiation of human macrophages into monocyte-like cells has been shown to be induced by bacterial toxins that elevate cAMP”

    From Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis (2025) · cites this paper as [52]

    The section on cAMP in alcoholic liver disease discusses cAMP levels and inflammatory responses in monocytes and macrophages, but not macrophage de-differentiation. Searches for macrophages becoming monocyte-like cells and for cAMP-elevating bacterial toxins found no passage addressing the claimed transformation. (LLM, conf=0.72)

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Authors
Wahlang, B., McClain, C., Barve, S., & Gobejishvili, L.
Affiliations
University of Louisville (US)
Corresponding author
Gobejishvili, Leila
Venue
Cellular Signalling
Publisher
Elsevier BV
Published
2018-09
Volume
49
Pages
105-115
ISSN
0898-6568 (ISSN-L)
OpenAlex
W2808536863
Cited by
168
References
183
Citations by year
2026: 13 · 2025: 43 · 2024: 23 · 2023: 20 · 2022: 20 · 2021: 14 · 2020: 20 · 2019: 13 · 2018: 1 · 2017: 1
FWCI
1.18
Type
journal article
Language
en
Update notices
erratum (2019-01-01)
Open access
Locations
  • Cellular Signalling (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (NIAAA) (R44AA021331 (LG), U01AA021901 (CM), P50AA024337 (CM))
  • National Institute of General Medical Sciences (NIGMS) (P20GM113226 (CM))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
cAMP signaling, phosphodiesterase, phosphodiesterase-4 inhibitors, non-alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis, hepatic steatosis, liver inflammation, second messenger signaling
MeSH terms
Cyclic AMP, Animals, Humans, Liver, Liver Diseases, Alcoholic, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Signal Transduction, Non-alcoholic Fatty Liver Disease

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