Tributyrin Mitigates Ethanol-Induced Lysine Acetylation of Histone-H3 and p65-NFκB Downregulating CCL2 Expression and Consequent Liver Inflammation and Injury

Author:

Ghare Smita S.123,Charpentier Benjamin T.24,Ghooray Dushan T.123,Zhang Jingwen123,Vadhanam Manicka V.123,Reddy Sreelatha123,Joshi-Barve Swati123,McClain Craig J.1235ORCID,Barve Shirish S.123

Affiliation:

1. Department of Medicine, University of Louisville, Louisville, KY 40202, USA

2. UofL Alcohol Center, University of Louisville, Louisville, KY 40202, USA

3. UofL Hepatobiology COBRE, University of Louisville, Louisville, KY 40202, USA

4. Department of Anatomical Science and Neurobiology, University of Louisville, Louisville, KY 40202, USA

5. Robley Rex VA Medical Center, University of Louisville, Louisville, KY 40202, USA

Abstract

Purpose: Chemokine-driven leukocyte infiltration and sustained inflammation contribute to alcohol-associated liver disease (ALD). Elevated hepatic CCL2 expression, seen in ALD, is associated with disease severity. However, mechanisms of CCL2 regulation are not completely elucidated. Post-translational modifications (PTMs) of proteins, particularly acetylation, modulate gene expression. This study examined the acetylation changes of promoter-associated histone-H3 and key transcription factor-NFκB in regulating hepatic CCL2 expression and subsequent inflammation and injury. Further, the effect of therapeutic modulation of the acetylation state by tributyrin (TB), a butyrate prodrug, was assessed. Methods: Hepatic CCL2 expression was assessed in mice fed control (PF) or an ethanol-containing Lieber–DeCarli (5% v/v, EF) diet for 7 weeks with or without oral administration of tributyrin (TB, 2 g/kg, 5 days/week). A chromatin immunoprecipitation (ChIP) assay evaluated promoter-associated modifications. Nuclear association between SIRT1, p300, and NFκB-p65 and acetylation changes of p65 were determined using immunoprecipitation and Western blot analyses. A Student’s t-test and one-way ANOVA determined the significance. Results: Ethanol significantly increased promoter-associated histone-H3-lysine-9 acetylation (H3K9Ac), reflecting a transcriptionally permissive state with a resultant increase in hepatic CCL2 mRNA and protein expression. Moreover, increased lysine-310-acetylation of nuclear RelA/p65 decreased its association with SIRT1, a class III HDAC, but concomitantly increased with p300, a histone acetyltransferase. This further led to enhanced recruitment of NF-κB/p65 and RNA polymerase-II to the CCL2 promoter. Oral TB administration prevented ethanol-associated acetylation changes, thus downregulating CCL2 expression, hepatic neutrophil infiltration, and inflammation/ injury. Conclusion: The modulation of a protein acetylation state via ethanol or TB mechanistically regulates hepatic CCL2 upregulation in ALD.

Funder

National Institute Of General Medical Sciences of the National Institutes of Health

National Institute On Alcohol Abuse and Alcoholism of the National Institutes of Health

Publisher

MDPI AG

Subject

Food Science,Nutrition and Dietetics

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