Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hakeem A.N.; Kamal M.M.; Tawfiq R.A.; Abdelrahman B.A.; Hammam O.A.; Elmazar M.M.; El-Khatib A.S.; Attia Y.M.

Journal: Biomedicine and Pharmacotherapy

Publisher: Elsevier Masson s.r.l.

Publication Date: January 2023

Volume / Issue: Volume 157

Article No.: 114050

ISSN: 7533322

DOI: 10.1016/j.biopha.2022.114050

Scopus: View on Scopus

PubMed: 36462310

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Hakeem A.N., Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Kamal M.M., The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt, Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Tawfiq R.A., Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Abdelrahman B.A., Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Hammam O.A., Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt; Elmazar M.M., Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; El-Khatib A.S., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Attia Y.M., Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt

Abstract

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH. © 2022 The Authors

Keywords

Intestinal permeability; Macrophage polarization; NASH; PPAR; STAT3; TLR4; Humans; Interleukin-10; Liver; Macrophages; NF-kappa B; Non-alcoholic Fatty Liver Disease; PPAR alpha; PPAR delta; STAT3 Transcription Factor; Toll-Like Receptor 4; arginase 1; claudin 1; elafibranor; gamma interferon; I kappa B kinase alpha; immunoglobulin enhancer binding protein; inducible nitric oxide synthase; interleukin 10; lipopolysaccharide binding protein; occludin; STAT3 protein; toll like receptor 4; triacylglycerol; 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid; peroxisome proliferator activated receptor alpha; peroxisome proliferator activated receptor delta; STAT3 protein, human; TLR4 protein, human; animal experiment; animal model; animal tissue; Article; colon tissue; controlled study; dextran sulfate sodium-induced colitis; drug efficacy; drug mechanism; enteritis; Hep-G2 cell line; high-fat diet-induced steatohepatitis; histopathology; ileum; ileum tissue; immunomodulation; immunoreactivity; in vitro study; intestine function; intestine function disorder; intestine mucosa permeability; lipid liver level; lipid storage; liver tissue; M2 macrophage; macrophage function; male; mouse; nonhuman; oil red o staining; protein blood level; protein expression level; protein phosphorylation; signal transduction; staining; treatment response; triacylglycerol level; human; macrophage; metabolism; nonalcoholic fatty liver

Citation Information

Scopus Citations: 22

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