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Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents

ABSTRACT: Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE129389 | GEO | 2019/08/20

REPOSITORIES: GEO

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Project description:Nonalcoholic fatty liver disease (NAFLD) is becoming a primary cause of liver damage in Western society. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD and may lead to liver cancer. Our previous long-term murine studies have shown the beneficial role of Aquamin, a red marine algae-derived (calcium, magnesium, additional trace elements-rich) supplement, in reducing liver injury and decreasing liver tumor incidence. The main objective of the study was to determine how manifestations and effects of NASH can be mitigated using Aquamin. We hypothesized that mice on a high-fat Western diet (HFWD) with minerals would exhibit less liver injury than mice on a HFWD without minerals. Methods: Two cohorts of MS-NASH mice (8-week-old) were placed on a HFWD with and without minerals for 16 weeks. An additional cohort of MS-NASH mice on the same HFWD was treated with obeticholic acid (OCA). C57BL/6 mice on a regular chow were included as a control. During the in-life phase of the study, weight changes were assessed weekly. At termination, livers were histologically assessed for steatosis and fibrosis by using hematoxylin and eosin, and picrosirius red staining. Liver tissue samples were also subjected to tandem mass tag (TMT) mass-spectroscopic proteomics for protein expression profile in individual mice. Results: Mice on HFWD gained more weight than mice on control diet, but there was no overall change in weight for mice on HFWD, irrespective of interventions. On histological assessment, there was no difference in steatosis between the two high-fat groups, but mice on Aquamin showed reduced picrosirius red staining or collagen deposition as compared to placebo on HFWD mice. Regarding proteomic profile, there was a clear distinction among control and HFWD groups. Placebo (on HFWD) mice were used for comparison. Aquamin intervention altered 91 proteins while OCA altered 84 proteins in liver samples with a 2-fold change. Of these, 57 proteins were common between Aquamin and OCA. Most of the proteins were upregulated. Aquamin upregulated 39 unique pathways (with a p-value <0.05) as assessed by the Reactome database. Some of the pathways significantly impacted by Aquamin were formation of cornified envelope; keratinization; gap junction assembly; type I hemidesmosome assembly; apoptosis-related; plasma lipoprotein assembly, remodeling and clearance; and hedgehog “off” state pathways. Proteins downregulated by OCA are mainly involved in the synthesis of bile acids and bile salts. Conclusion: The addition of dietary minerals may play a protective role in interfering with downstream advancement from steatosis to NASH. Our studies provide mechanistic insight into how mineral supplementation may contribute to the reduction in liver injury and tumor formation (one of the most devastating consequences) of fatty liver disease in the context of HFWD-induced steatosis.

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Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents

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