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FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.

ABSTRACT: Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3-day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real-time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT-777 decreased hepatic macrovesicular steatosis and protected from ethanol-induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT-767, or INT-777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin-1? mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate-induced activation of protein kinase A. Conclusion: OCA, INT-767, or INT-777 administration is effective in reducing acute and chronic ethanol-induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

SUBMITTER: Iracheta-Vellve A

PROVIDER: S-EPMC6211332 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.

Iracheta-Vellve Arvin A Calenda Charles D CD Petrasek Jan J Ambade Aditya A Kodys Karen K Adorini Luciano L Szabo Gyongyi G

Hepatology communications 20181015 11

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation p ...[more]

PMID: 30411084

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Project description:Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. To better understand how PCB126 promoted alcohol-associated liver disease (ALD) in our previous model, the current study utilized a phosphoproteomic approach for hypothesis generation regarding mechanisms of action. Briefly, male C57B/6J mice were exposed to 0.2 mg/kg polychlorinated biphenyl PCB126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were harvested during euthanasia and tissue collection, snap frozen in liquid nitrogen, and then were archived in a -80C freezer. For phosphoproteome analysis, six random liver tissues from four groups (N=24) were homogenized in 2% sodium dodecyl sulfate (SDS) radioimmunoprecipitation (RIPA) buffer with 1X HALT protease and phosphatase inhibitors. Lysates were trypsinized at a 1:20 (enzyme:sample) ratio and prepared following ProtiFi S-Trap mini spin column digestion protocol. Phospho-peptides were enriched with MagReSyn titanium ion - immobilized metal affinity chromatography (Ti-IMAC) microparticles following ReSyn Biosciences MagReSyn Ti-IMAC protocol. Samples were then purified using C18 PROTO 300 A Ultra MicroSpin columns, dried under a SpeedVac, and stored at -80C prior to peptide concentration assessment. Digests were fractionated by UPLC nanoflow liquid chromatography using PepMap RSLC C18 EASY-spray separating column at 40C with a 90-minute linear gradient. Eluates were introduced into an Exploris480 using an EASY-spray source (320C and 1.8kV). Full MS-ddMS2 method with a 3 second cycle time was generated in Xcalibur (v4.5.445.18) operating in positive polarity. RAW data files were separately searched in PeaksXpro (Bioinformatics Solutions Inc.; Waterloo, ON, Canada) using Denovo, PeaksDB, and PeaksPTM algorithms against the UniprotKB Mus musculus canonical protein sequences (proteomics ID: UP000000589) downloaded March 17, 2023. Label Free Quantification algorithm was then used with PeaksPTM results utilizing a mass error tolerance of 10 ppm and retention time shift tolerance of 6-minutes. Peptides were accepted at a 1% FDR threshold for consideration by the Label Free Quantification algorithm.

Project description:IntroductionAlcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse promotes acute lung injury are poorly understood. These gaps in our understanding are due, at least in part, to limitations of animal models to recapitulate human alcohol consumption. Recently, a new model of chronic plus binge alcohol exposure was developed that is hypothesized to better model drinking patterns of individuals with alcohol use disorders. Specifically, this paradigm models chronic consumption coupled with periodic bouts of heavy drinking. The impacts of this alcohol-exposure regimen on the lung are uncharacterized. Therefore, the goal of this study was to examine lung injury and inflammation in a well-characterized experimental model of chronic + binge alcohol exposure.Methods10-week-old male C57Bl6/J mice were administered ethanol-containing (or isocaloric control) liquid diet for 10 days, followed by a single ethanol gavage (5 g/kg). Lung inflammation and pulmonary function were assessed.ResultsTen days of ethanol-containing liquid diet alone (chronic) did not detectably affect any variables measured. However, ethanol diet plus gavage (chronic + binge) caused neutrophils to accumulate in the lung tissue and in the bronchoalveolar lavage fluid 24 h post-binge. This inflammatory cell recruitment was associated with airway hyper-responsiveness to inhaled methacholine, as indicated by elevated resistance, Newtonian resistance, and respiratory resistance.ConclusionsTaken together, the novel findings reveal that ethanol alone, absent of any secondary inflammatory insult, is sufficient to produce inflammation in the lung. Although these changes were relatively mild, they were associated with functional changes in the central airways. This animal model may be useful in the future for identifying mechanisms by which alcohol abuse sensitizes at-risk individuals to lung injury.

Dataset Information

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.

Publications

FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.

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