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

Rodríguez, Walter; Wahlang, Banrida; Wang, Yali; Zhang, Jingwen; Vadhanam, Manicka V.; Joshi‐Barve, Swati; Bauer, Philip M.; Cannon, Robert M.; Ahmadi, Ali; Sun, Zhaoli; Cameron, Andrew; Barve, Shirish; Maldonado, Claudio; McClain, Craig J.; Gobejishvili, Leila

doi:10.1002/hep.30761

Cited by 39 publications

(51 citation statements)

References 45 publications

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“…We used a PDE4-specific inhibitor as well as Pde4b knockout mice and showed that the ethanol-mediated decrease in CPT1A expression was prevented via the PPARα/PGC1α/SIRT1 pathway in an in vivo mouse model of chronic Liber deCarli feeding for four weeks [ 111 ]. Recently, we recapitulated the same results in a chronic ethanol binge (10 plus one, NIAAA) model [ 112 ]. Moreover, a single administration of PDE4 inhibitor prevented the ethanol-mediated decrease in cAMP levels and attenuated liver injury.…”

Section: Camp Signaling In Aldsupporting

confidence: 58%

“…In this study, the effect of ethanol on hepatocyte and liver cAMP levels was not evaluated. Later, work from our group showed that chronic ethanol feeding significantly decreased cAMP levels in mouse livers as well as in hepatocytes isolated from ethanol-fed mice [ 111 , 112 ]. However, the relative decrease was larger in the whole liver.…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

“…These results indicated that ethanol might affect other cell types in the liver, which agrees with our previous studies demonstrating that ethanol decreases cAMP levels in Kupffer cells [ 113 ]. Importantly, we observed that ethanol decreased hepatic cAMP levels by significantly upregulating cAMP-specific PDE4 both in vivo and in in vitro primary rat and mouse hepatocytes [ 111 , 112 ]. Decreased cAMP levels resulted in lower pCREB levels and decreased CPT1A expression.…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

“…Our observations showed that PDE4 inhibition was protective due to decreased oxidative and endoplasmic reticulum stress and hepatocyte apoptosis in ethanol-fed mice. Importantly, human livers from alcohol-associated hepatitis patients have much higher expression of PDE4 and decreased cAMP levels [ 112 ]. These observations strongly suggest that PDE4-mediated dysregulation of cAMP signaling might play a pathogenic role in human ALD.…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

“…Chromatin immunoprecipitation studies confirmed that Misoprostol treatment modulated transcription factor and RNA Polymerase II binding, resulting in changes in TNF and IL-10 mRNA levels [ 131 ]. More recently, we evaluated the effect of the FDA-approved PDE4-specific inhibitor, Roflumilast, on LPS-inducible TNFα and IL-1β production in ex vivo studies using whole blood from AH patients [ 112 ]. We observed the significant attenuation of both TNF and IL-1β levels by Roflumilast [ 112 ].…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

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cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.

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Section: Camp Signaling In Aldsupporting

confidence: 58%

Section: Camp Signaling In Aldmentioning

confidence: 99%

Section: Camp Signaling In Aldmentioning

confidence: 99%

Section: Camp Signaling In Aldmentioning

confidence: 99%

Section: Camp Signaling In Aldmentioning

confidence: 99%

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cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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Cathelicidin‐related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation

Zhao

Shao

et al. 2020

The Journal of Pathology

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Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp −/−) and wild-type (WT) mice were subjected to binge-on-chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum/plasma and hepatic tissue samples from human subjects with alcohol use disorder and/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)-1β levels. Although Camp −/− mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL-1β in alcohol use disorder patients with ALD and were increased in Camp −/− mice fed alcohol. In vitro studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL-1β concentrations and rescued the liver from alcohol-induced damage in both WT and Camp −/− mice. In summary, CRAMP exhibited a protective role against binge-on-chronic alcohol-induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD.

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Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration

Elnagdy,

Wang,

Rodriguez

et al. 2023

The Journal of Pathology

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Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho‐specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho‐associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFβ1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP‐degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFβ1 levels were highly correlated with PDE4 expression. TGFβ1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC‐specific agonist decreased TGFβ1‐mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis‐related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.

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

Cited by 39 publications

References 45 publications

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

Cathelicidin‐related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration

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