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Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH.

ABSTRACT: Obeticholic acid (OCA) and elafibranor (ELA) are selective and potent agonists for the farnesoid X receptor (FXR) and dual peroxisome proliferator-activated receptor ?/? (PPAR-?/?), respectively. Both agents have demonstrated clinical efficacy in nonalcoholic steatohepatitis (NASH). The present study used OCA and ELA to compare the effects of mono- and combination therapies on metabolic and histological endpoints in Lepob/ob mice with established diet-induced and biopsy-confirmed NASH (ob/ob-NASH). ob/ob-NASH mice were fed the AMLN diet high in trans-fat, fructose and cholesterol for 15 weeks, whereafter they received vehicle, OCA (30?mg/kg, PO, QD), ELA (3, 10?mg/kg, PO, QD), or combinations (OCA?+?ELA) for eight weeks. Within-subject comparisons were performed on histomorphometric changes, including fractional area of liver fat, galectin-3 and Col1a1. OCA and ELA monotherapies improved all quantitative histopathological parameters and OCA?+?ELA combinations exerted additive effects on metabolic and histological endpoints. In agreement with their different molecular mechanisms of action, OCA and ELA monotherapies elicited distinct hepatic gene expression profiles and their combination led to profound transcriptome changes associated with further improvements in lipid handling and insulin signaling, suppression of immune responses and reduced extracellular matrix formation. In conclusion, these findings provide preclinical proof-of-concept for combined FXR and PPAR-?/? agonist-based therapies in NASH.

SUBMITTER: Roth JD

PROVIDER: S-EPMC6588626 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH.

Roth Jonathan D JD Veidal Sanne S SS Fensholdt Louise K D LKD Rigbolt Kristoffer T G KTG Papazyan Romeo R Nielsen Jens Christian JC Feigh Michael M Vrang Niels N Young Mark M Jelsing Jacob J Adorini Luciano L Hansen Henrik H HH

Scientific reports 20190621 1

Obeticholic acid (OCA) and elafibranor (ELA) are selective and potent agonists for the farnesoid X receptor (FXR) and dual peroxisome proliferator-activated receptor α/δ (PPAR-α/δ), respectively. Both agents have demonstrated clinical efficacy in nonalcoholic steatohepatitis (NASH). The present study used OCA and ELA to compare the effects of mono- and combination therapies on metabolic and histological endpoints in Lep<sup>ob/ob</sup> mice with established diet-induced and biopsy-confirmed NASH ...[more]

PMID: 31227742

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Project description:BackgroundSuppression of cardiac iinflammasome, which can be inhibited by Farnesoid X receptor (FXR) agonist, can ameliorate cardiac inflammation and fibrosis. Increased cardiac inflammasome decrease the abundance of regulatory T (Treg) cells and exacerbate cardiac dysfunction. Interaction between cardiomyocytes and Treg cells is involved in the development of nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction.AimsThis study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction.MethodsThe in vivo and in vitro mechanisms and effects of two weeks of OCA treatment on inflammasome and Treg dysregulation-related cardiac dysfunction in NASH mice (NASH-OCA) at systemic, tissue and cellular levels were investigated.ResultsThe OCA treatment suppressed the serum and cardiac inflammasome levels, reduced the cardiac infiltrated CD3+ T cells, increased the cardiac Treg-represented anti-inflammatory cytokines (IL-10/IL-10R) and improved cardiac inflammation, fibrosis and function [decreased left ventricle (LV) mass and increased fractional shortening (FS)] in NASH-OCA mice. The percentages of OCA-decreased cardiac fibrosis and OCA-increased FS were positively correlated with the percentage of OCA-increased levels of cardiac FXR and IL-10/IL-10R. In the Treg cells from NASH-OCA mice spleen, in comparison with the Treg cells of the NASH group, higher intracellular FXR but lower inflammasome levels, and more proliferative/active and less apoptotic cells were observed. Incubation of H9c2 cardiomyoblasts with Treg-NASHcm [supernatant of Treg from NASH mice as condition medium (cm)], increased inflammasome levels, decreased the proliferative/active cells, suppressed the intracellular FXR, and downregulated differentiation/contraction marker. The Treg-NASHcm-induced hypocontractility of H9c2 can be attenuated by co-incubation with OCA, and the OCA-related effects were abolished by siIL-10R pretreatment.ConclusionsChronic FXR activation with OCA is a potential strategy for activating IL-10/IL-10R signalling, reversing cardiac regulatory T cell dysfunction, and improving inflammasome-mediated NASH-related cardiac dysfunction.

Dataset Information

Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH.

Publications

Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH.

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