Introduction
Non-alcohol fatty liver disease (NAFLD) describes a spectrum of liver abnormalities ranging from fatty liver or simple steatosis to non-alcoholic steatohepatitis (NASH) without or with hepatic fibrosis. NAFLD is a common condition, with a global prevalence of approximately 25 %, strongly linked to obesity, diabetes and systemic dyslipidemia (Younossi, Koenig et al, 2016). NASH is characterized by strong hepatic steatosis, lobular inflammation and hepatocyte ballooning (Diehl and Day, 2017). The prevalence of NASH is increasing (Estes, Razavi et al, 2018; Estes, Anstee et al, 2018), and NASH with advanced fibrosis is associated with a strong increase in liver-related and overall mortality (Ekstedt, Hagström et al, 2015; Dulai, Singh et al, 2017). No pharmacological therapy is approved for the treatment of NASH, though some experimental drugs are currently in later stages of clinical development (Garber, 2019). First-line therapy is lifestyle intervention with a focus on weight loss (Chalasani, Younossi et al, 2018). Thus, new therapies for advanced NASH with fibrosis are urgently needed.
Thyroid hormone receptor ß (THR-ß) is the most abundant thyroid hormone receptor isoform in the liver but also expressed in other tissues. Its expression in the liver is reduced in patients with NASH (Krause, Grohs et al, 2018). Activation of hepatic THR-ß is associated with systemic lipid lowering, increased bile acid synthesis and fat oxidation (Sinha, Bruinstroop et al, 2019). Liver-directed agonists with high selectivity for THR-ß over THR-α have been generated (Kelly, Pietranico-Cole et al, 2014; Erion, Cable et al, 2007) and showed metabolic benefits in preclinical models of diabetes and obesity including reduced hepatic steatosis and inflammation (Sinha, Bruinstroop, et al, 2019). However, there is little information on their activity in obese animals with manifest NASH and fibrosis. Recently, resmetirom (MGL-3196) was evaluated in a 36-week clinical phase-2 study in patients with biopsy-confirmed NASH, was well tolerated and led to a significant reduction in hepatic fat fraction, circulating LDL cholesterol and triglycerides, and a higher rate of NASH resolution compared to placebo (Harrison, Bashir et al, Lancet 2019).
Here we report the evaluation of resmetirom as a prototype of a liver-directed, selective THR-ß agonist in a diet-induced obese (DIO) and biopsy-confirmed mouse model of advanced NASH with fibrosis. Our results reflect clinical findings of reduced hepatic steatosis, liver injury, circulating cholesterol and histological NAFLD activity score (NAS). In addition, we demonstrate changes in expression of THR-ß regulated genes. Of note, these effects were observed at a low dose of 3 mg/kg that was not associated with body weight loss. This is, to our knowledge, the first study describing the effects of resmetirom in a pre-clinical model of NASH, fully replicating recent clinical observations.