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

• Published in: Biomedicine & pharmacotherapy 2023-01, Vol.157, p.114050, Article 114050
• Main Authors: Hakeem, Andrew N., Kamal, Mohamed M., Tawfiq, Rasha A., Abdelrahman, Basma A., Hammam, Olfat A., Elmazar, Mohamed M., El-Khatib, Aiman S., Attia, Yasmeen M.
• Format: Article
• Language: English
• Subjects: Humans; Interleukin-10 - metabolism; Intestinal permeability; Liver - metabolism; Macrophage polarization; Macrophages - metabolism; NASH; NF-kappa B - metabolism; Non-alcoholic Fatty Liver Disease - metabolism; PPAR; PPAR alpha - metabolism; PPAR delta - metabolism; STAT3; STAT3 Transcription Factor - metabolism; TLR4; Toll-Like Receptor 4 - metabolism
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.114050

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. [Display omitted] •ELA reduces steatosis in vitro and improves NASH hallmarks in vivo.•ELA curbs hepatic TLR4/NF-κB signaling in HFD/DSS-induced NASH.•ELA modulates MP signals, viz., TLR4/IFNγ and IL-10/STAT3 signaling in ileum.•ELA improves barrier integrity by skewing ileal macrophages to the M2 phenotype.