FXR activation remodels hepatic and intestinal transcriptional landscapes in non-alcoholic steatohepatitis

Abstract: The progression of simple steatosis to non-alcoholic steatohepatitis (NASH) has emerged as a significant health concern. The activation of FXR shows promise in countering this transition and its detrimental consequences. However, the specific alterations within the NASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse NASH samples, we identified central perturbations within the NASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis, thus shedding light on the complex molecular mechanisms underlying NASH progression. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and publicly available human datasets, we determined that hepatic FXR activation effectively ameliorated NASH by reversing the dysregulated metabolic and inflammatory networks implicated in NASH pathogenesis. This mitigation encompassed resolving fibrosis, reducing immune infiltration, and creating an immune microenvironment that mirrors the positive trends observed in clinical disease progression. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of NASH at a transcriptional level and highlights the complex interplay between FXR activation and both NASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.