Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies
Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components o...
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/2079-7737/12/10/1321 |
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| author | Diego Montoya-Durango Mary Nancy Walter Walter Rodriguez Yali Wang Julia H. Chariker Eric C. Rouchka Claudio Maldonado Shirish Barve Craig J. McClain Leila Gobejishvili |
| author_facet | Diego Montoya-Durango Mary Nancy Walter Walter Rodriguez Yali Wang Julia H. Chariker Eric C. Rouchka Claudio Maldonado Shirish Barve Craig J. McClain Leila Gobejishvili |
| author_sort | Diego Montoya-Durango |
| collection | DOAJ |
| description | Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH. |
| first_indexed | 2024-03-10T21:25:10Z |
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| last_indexed | 2024-03-10T21:25:10Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-18569421050f4eb4885efe87cba9f9c42023-11-19T15:43:39ZengMDPI AGBiology2079-77372023-10-011210132110.3390/biology12101321Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted TherapiesDiego Montoya-Durango0Mary Nancy Walter1Walter Rodriguez2Yali Wang3Julia H. Chariker4Eric C. Rouchka5Claudio Maldonado6Shirish Barve7Craig J. McClain8Leila Gobejishvili9Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Neuroscience Training, University of Louisville, Louisville, KY 40290, USAKY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40290, USADepartment of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40290, USADepartment of Physiology, School of Medicine, University of Louisville, Louisville, KY 40290, USABackground: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.https://www.mdpi.com/2079-7737/12/10/1321alcohol-associated steatohepatitislivercAMPcGMPphosphodiesterases |
| spellingShingle | Diego Montoya-Durango Mary Nancy Walter Walter Rodriguez Yali Wang Julia H. Chariker Eric C. Rouchka Claudio Maldonado Shirish Barve Craig J. McClain Leila Gobejishvili Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies Biology alcohol-associated steatohepatitis liver cAMP cGMP phosphodiesterases |
| title | Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies |
| title_full | Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies |
| title_fullStr | Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies |
| title_full_unstemmed | Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies |
| title_short | Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies |
| title_sort | dysregulated cyclic nucleotide metabolism in alcohol associated steatohepatitis implications for novel targeted therapies |
| topic | alcohol-associated steatohepatitis liver cAMP cGMP phosphodiesterases |
| url | https://www.mdpi.com/2079-7737/12/10/1321 |
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