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Published on: April 16, 2019
Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice
Szu-Yu Liu1,2, Chia-Chang Huang2,3, Ying-Ying Yang1,2
1Department of Medical Education, Clinical Innovation Center, Medical Innovation and Research Office, Taipei Veterans General Hospital, Taipei, Taiwan.
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.
Insights
Farnesoid X receptor (FXR) agonist obeticholic acid (OCA) treatment improves nonalcoholic steatohepatitis (NASH)-related cardiac dysfunction by suppressing inflammasome and enhancing regulatory T (Treg) cells. This approach ameliorates cardiac inflammation and fibrosis, offering a potential therapeutic strategy.
Area of Science:
- Cardiovascular Medicine
- Hepatology
- Immunology
Background:
- Nonalcoholic steatohepatitis (NASH) is linked to cardiac dysfunction.
- Cardiac inflammasome activation exacerbates inflammation, fibrosis, and dysfunction, partly by reducing regulatory T (Treg) cells.
- Farnesoid X receptor (FXR) agonists can inhibit inflammasome activity.
Purpose of the Study:
- To evaluate if the FXR agonist obeticholic acid (OCA) improves cardiac dysfunction in NASH.
- To investigate the mechanisms underlying OCA's effects on inflammasome and Treg cells in NASH-related cardiac issues.
Main Methods:
- Two weeks of OCA treatment in NASH mice (in vivo and in vitro).
- Assessment of systemic, tissue, and cellular levels of inflammasome, Treg cells, and cardiac function markers.
- Co-incubation experiments with H9c2 cardiomyoblasts and Treg-derived conditioned medium.
Main Results:
- OCA suppressed serum and cardiac inflammasome, reduced T cell infiltration, and increased Treg-associated IL-10/IL-10R.
- Cardiac inflammation, fibrosis, and dysfunction (e.g., reduced LV mass, improved FS) were ameliorated.
- OCA treatment enhanced Treg cell proliferation and reduced apoptosis, while protecting cardiomyocytes from Treg-NASHcm-induced dysfunction.
Conclusions:
- Chronic FXR activation with OCA is a promising strategy for NASH-related cardiac dysfunction.
- OCA enhances IL-10/IL-10R signaling and reverses Treg cell dysfunction.
- This approach targets inflammasome-mediated pathways to improve cardiac health in NASH.
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