Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary
Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activ...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-01-01
|
| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X19301419 |
| _version_ | 1818512080502784000 |
|---|---|
| author | Hridgandh Donde Smita Ghare Swati Joshi-Barve JingWen Zhang Manicka V. Vadhanam Leila Gobejishvili Pawel Lorkiewicz Sanjay Srivastava Craig J. McClain Shirish Barve |
| author_facet | Hridgandh Donde Smita Ghare Swati Joshi-Barve JingWen Zhang Manicka V. Vadhanam Leila Gobejishvili Pawel Lorkiewicz Sanjay Srivastava Craig J. McClain Shirish Barve |
| author_sort | Hridgandh Donde |
| collection | DOAJ |
| description | Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activity, attenuates hepatic steatosis and injury. The present study examined the beneficial effect of tributyrin/butyrate in attenuating ethanol-induced pathogenic epigenetic mechanisms affecting CPT-1A promoter–histone modifications and gene expression and hepatic steatosis/injury. Methods: Mice were fed a liquid Lieber-DeCarli diet (Research Diet Inc, New Brunswick, NJ) with or without ethanol for 4 weeks. In a subset of mice, tributyrin (2 g/kg) was administered orally by gavage. Primary rat hepatocytes were treated with 50 mmol/L ethanol and/or 2 mmol/L butyrate. Gene expression and epigenetic modifications at the CPT-1A promoter were analyzed by chromatin immunoprecipitation analysis. Results: In vivo, ethanol induced hepatic CPT-1A promoter histone H3K9 deacetylation, which is indicative of a repressive chromatin state, and decreased CPT-1A gene expression. Our data identified HDAC1 as the predominant HDAC causing CPT-1A promoter histone H3K9 deacetylation and epigenetic down-regulation of gene expression. Significantly, Specificity Protein 1 (SP1) and Hepatocyte Nuclear Factor 4 Alpha (HNF4α) participated in the recruitment of HDAC1 to the proximal and distal regions of CPT-1A promoter, respectively, and mediated transcriptional repression. Importantly, butyrate, a dietary HDAC inhibitor, attenuated ethanol-induced recruitment of HDAC1 and facilitated p300-HAT binding by enabling SP1/p300 interaction at the proximal region and HNF4α/peroxisomal proliferator-activated receptor-γ coactivator-1α/p300 interactions at the distal region, leading to promoter histone acetylation and enhanced CPT-1A transcription. Conclusions: This study identifies HDAC1-mediated repressive epigenetic mechanisms that underlie an ethanol-mediated decrease in CPT-1A expression. Importantly, tributyrin/butyrate inhibits HDAC1, rescues CPT-1A expression, and attenuates ethanol-mediated hepatic steatosis and injury, suggesting its potential use in therapeutic strategies for alcoholic liver disease. |
| first_indexed | 2024-12-10T23:41:35Z |
| format | Article |
| id | doaj.art-f3a042fee3bf4843a2824a67ecfa98b0 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-10T23:41:35Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-f3a042fee3bf4843a2824a67ecfa98b02022-12-22T01:29:02ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-0194569585Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummaryHridgandh Donde0Smita Ghare1Swati Joshi-Barve2JingWen Zhang3Manicka V. Vadhanam4Leila Gobejishvili5Pawel Lorkiewicz6Sanjay Srivastava7Craig J. McClain8Shirish Barve9Department of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky; Hepatobiology and Toxicology Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky; Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky; Hepatobiology and Toxicology Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Superfund Research Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Superfund Research Center, University of Louisville, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky; Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; Robley Rex Veterans Affairs Medical Center, Louisville, KentuckyDepartment of Medicine, University of Louisville, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky; Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; Correspondence Address correspondence to: Shirish Barve, PhD, Department of Medicine, Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, CTR Building, Room 515, 505 S Hancock Street, Louisville, Kentucky 40202. fax: (502) 852-8927.Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activity, attenuates hepatic steatosis and injury. The present study examined the beneficial effect of tributyrin/butyrate in attenuating ethanol-induced pathogenic epigenetic mechanisms affecting CPT-1A promoter–histone modifications and gene expression and hepatic steatosis/injury. Methods: Mice were fed a liquid Lieber-DeCarli diet (Research Diet Inc, New Brunswick, NJ) with or without ethanol for 4 weeks. In a subset of mice, tributyrin (2 g/kg) was administered orally by gavage. Primary rat hepatocytes were treated with 50 mmol/L ethanol and/or 2 mmol/L butyrate. Gene expression and epigenetic modifications at the CPT-1A promoter were analyzed by chromatin immunoprecipitation analysis. Results: In vivo, ethanol induced hepatic CPT-1A promoter histone H3K9 deacetylation, which is indicative of a repressive chromatin state, and decreased CPT-1A gene expression. Our data identified HDAC1 as the predominant HDAC causing CPT-1A promoter histone H3K9 deacetylation and epigenetic down-regulation of gene expression. Significantly, Specificity Protein 1 (SP1) and Hepatocyte Nuclear Factor 4 Alpha (HNF4α) participated in the recruitment of HDAC1 to the proximal and distal regions of CPT-1A promoter, respectively, and mediated transcriptional repression. Importantly, butyrate, a dietary HDAC inhibitor, attenuated ethanol-induced recruitment of HDAC1 and facilitated p300-HAT binding by enabling SP1/p300 interaction at the proximal region and HNF4α/peroxisomal proliferator-activated receptor-γ coactivator-1α/p300 interactions at the distal region, leading to promoter histone acetylation and enhanced CPT-1A transcription. Conclusions: This study identifies HDAC1-mediated repressive epigenetic mechanisms that underlie an ethanol-mediated decrease in CPT-1A expression. Importantly, tributyrin/butyrate inhibits HDAC1, rescues CPT-1A expression, and attenuates ethanol-mediated hepatic steatosis and injury, suggesting its potential use in therapeutic strategies for alcoholic liver disease.http://www.sciencedirect.com/science/article/pii/S2352345X19301419Epigenetic Promoter ModificationGene RegulationAlcoholic Liver DiseaseHepatocytes |
| spellingShingle | Hridgandh Donde Smita Ghare Swati Joshi-Barve JingWen Zhang Manicka V. Vadhanam Leila Gobejishvili Pawel Lorkiewicz Sanjay Srivastava Craig J. McClain Shirish Barve Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary Cellular and Molecular Gastroenterology and Hepatology Epigenetic Promoter Modification Gene Regulation Alcoholic Liver Disease Hepatocytes |
| title | Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary |
| title_full | Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary |
| title_fullStr | Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary |
| title_full_unstemmed | Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary |
| title_short | Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and InjurySummary |
| title_sort | tributyrin inhibits ethanol induced epigenetic repression of cpt 1a and attenuates hepatic steatosis and injurysummary |
| topic | Epigenetic Promoter Modification Gene Regulation Alcoholic Liver Disease Hepatocytes |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X19301419 |
| work_keys_str_mv | AT hridgandhdonde tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT smitaghare tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT swatijoshibarve tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT jingwenzhang tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT manickavvadhanam tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT leilagobejishvili tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT pawellorkiewicz tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT sanjaysrivastava tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT craigjmcclain tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary AT shirishbarve tributyrininhibitsethanolinducedepigeneticrepressionofcpt1aandattenuateshepaticsteatosisandinjurysummary |