# Effects of Obeticholic Acid Treatment on Primary Human Hepatocytes in a Novel Tri-Culture Model System

## TL;DR

This study examines how Obeticholic Acid affects liver cells in a new lab model, showing it reduces fat, inflammation, and fibrosis in diseased cells.

## Contribution

A novel tri-culture model system is used to evaluate OCA's effects on human liver cells with disease phenotypes.

## Key findings

- OCA reduced lipogenesis and triglyceride levels in both healthy and diseased hepatocytes.
- OCA lowered inflammatory and fibrotic markers in diseased hepatocytes.
- OCA altered gene expression of CYP3A4, CYP7A1, and BSEP in both healthy and diseased cells.

## Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing health concern worldwide. Human cell-based in vitro culture models that retain disease-relevant phenotypic pathways and responses to assess the efficacy and liability of new therapeutics are needed. Obeticholic Acid (OCA), a Farnesoid X Receptor agonist, has been identified for MAFLD treatment, and clinically shown to have anti-inflammatory and anti-fibrotic effects. In this study, healthy and disease-origin primary human hepatocytes (PHHs) were cultured in TruVivo®, an all-human hepatic system for 14 days and treated with OCA to determine its’ effects on lipogenic, inflammatory, and fibrogenic pathways. Decreases in lipogenesis and triglyceride levels were measured in OCA treated healthy and diseased PHHs. Significant decreases in CYP3A4 activity and gene expression were quantified. Macrophage marker expression, pro-inflammatory cytokines and fibrotic markers were lowered in OCA treated diseased PHHs. CYP7A1 gene expression decreased, while BSEP gene expression increased in OCA treated healthy and diseased PHHs. Overall, OCA treatment reduced lipogenic, inflammatory, and fibrogenic markers in diseased PHHs. Differences in the potency and efficacy of OCA against different disease-relevant pathways were observed in healthy and diseased PHHs indicating divergence of key regulatory mechanisms between healthy versus diseased phenotypes.