Abstract
Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD). Treatment with OCA effectively prevented chronic inflammation and liver fibrosis in WD-fed MC4R-KO mice with only marginal effect on body weight and hepatic steatosis. Hepatic crown-like structure (hCLS) is a unique histological structure characteristic of NASH, which triggers hepatocyte death-induced interstitial fibrosis. Intriguingly, treatment with OCA markedly reduced hCLS formation even after MC4R-KO mice developed NASH, thereby inhibiting the progression of liver fibrosis. As its mechanism of action, OCA suppressed metabolic stress-induced p53 activation and cell death in hepatocytes. Our findings in this study highlight the role of FXR in hepatocytes in the pathogenesis of NASH. Collectively, this study demonstrates the anti-fibrotic effect of OCA in a murine model of NASH with obesity and insulin resistance, which suggests the clinical implication for human NASH.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is recognized worldwide as the most prevalent chronic liver disease and is frequently accompanied with obesity and type 2 diabetes mellitus[1,2]
We found in this study that treatment with obeticholic acid (OCA) markedly suppresses hepatocyte death, hepatic crown-like structure (hCLS) formation and liver fibrosis with only marginal effects on body weight and hepatic steatosis
Since there is substantial evidence indicating the involvement of p53 and hepatocyte death in liver fibrosis in humans and rodents[28,29,30], we evaluated the effect of OCA on cell death using TdT mediated dUTP-biotin nick end labeling (TUNEL) staining
Summary
Non-alcoholic fatty liver disease (NAFLD) is recognized worldwide as the most prevalent chronic liver disease and is frequently accompanied with obesity and type 2 diabetes mellitus[1,2]. Several studies support the clinical relevance of OCA, among which a multicenter, randomized, placebo-controlled trial (the FLINT study) demonstrates that treatment with OCA improves the biochemical and histological features of NASH19–21 It is still unclear how OCA protects against NASH and which cell type is the main target of OCA, since stromal cells, such as HSCs and macrophages as well as parenchymal hepatocytes express FXR. In addition to the known phenotypes, such as obesity and insulin resistance, MC4R-KO mice on high-fat diet or Western diet (WD) progressively exhibit hepatic steatosis, NASH and multiple liver tumors Using this model, we have identified a unique histological structure termed “hepatic crown-like structure (hCLS)”, in which macrophages surround dead or dying hepatocytes with large lipid droplets, thereby activating HSCs to induce interstitial fibrosis[24]. Our findings highlight the role of FXR in hepatocytes in the pathogenesis of NASH and demonstrate the anti-fibrotic effect of OCA in a unique murine model of NASH with obesity and insulin resistance
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