Key result
Obeticholic acid treatment improved cardiac inflammation, fibrosis, and function in NASH mice by suppressing inflammasome levels and increasing anti-inflammatory cytokines.
Why the study?
Cardiomyocyte and Treg cell interactions contribute to NASH-related cardiac dysfunction, and it was unknown whether the FXR agonist obeticholic acid improves this dysfunction.
Does obeticholic acid improve cardiac dysfunction, inflammation, and fibrosis in a mouse model of NASH?
Does obeticholic acid improve cardiac dysfunction, inflammation, and fibrosis in a mouse model of NASH?
Chronic FXR activation with obeticholic acid ameliorates inflammasome-mediated cardiac dysfunction and fibrosis in a mouse model of NASH.
Answers are grounded in this paper and cite their sources.
May support FXR agonism in NASH-cardiac dysfunction; leaves open clinical translation pending trials.
BACKGROUND: Suppression 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. AIMS: This study evaluates whether the FXR agonist obeticholic acid (OCA) treatment improves NASH-associated cardiac dysfunction. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Chronic 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.
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Liu et al. (2022) studied NASH-associated cardiac dysfunction (n=34). Obeticholic acid vs. Vehicle (NASH group) was evaluated on Cardiac function (fractional shortening, LV mass) and cardiac inflammation/fibrosis. Obeticholic acid treatment improved cardiac inflammation, fibrosis, and function in NASH mice by suppressing inflammasome levels and increasing anti-inflammatory cytokines.
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