Obeticholic acid does not restore Western diet-induced alterations in hepatic mitochondrial respiration

Abstract

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects a significant portion of the global population, with mitochondrial dysfunction playing a pivotal role in its pathogenesis. Although FXR agonists such as obeticholic acid (OCA) have been studied as potential treatments for MASLD, the direct effects of OCA on the liver are still not fully understood. This study aimed to evaluate the effects of OCA in an in vivo model of MASLD.

Methods

Male C57BL/6 J mice were fed a control diet (CD) or a Western diet (WD) enriched with glucose and fructose in the drinking water for 36 weeks. During the final 3 weeks, mice received OCA (5 or 10 mg/kg/day) or vehicle. Liver histology, biochemical parameters, gene expression, mitochondrial enzymes activity and mitochondrial respiration were assessed.

Results

WD-fed mice exhibited increased body and liver weights and elevated aminotransferases, none of which were altered by OCA. OCA treatment did not significantly impact steatosis, inflammation, fibrosis, or hepatic lipid content. WD feeding reduced succinate-stimulated hepatic mitochondrial respiration, associated with decreased succinate dehydrogenase (SDH) expression and activity. OCA partially restored Sdh subunits B and C expression but did not significantly improve respirometric parameters.

Conclusion

Our findings consistently demonstrate that OCA administration in an established diet-induced murine model of MASLD does not improve hepatic steatosis or inflammation. Moreover, the WD-induced decrease in succinate-stimulated mitochondrial respiration was not ameliorated by OCA.