Dual Outcomes of Rosiglitazone Treatment on Fatty Liver

Abstract

In previous studies, it has been reported that rosiglitazone has opposing effects on nonalcoholic fatty liver disease. The purpose of the current study is to test the hypothesis that such opposing effects are related to different levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the liver. Using a gene transfer approach and mice fed a high-fat diet (HFD) as an animal model, we demonstrate that mice with low levels of PPAR-γ expression in the liver are resistant to HFD-induced development of fatty liver when treated with rosiglitazone. Conversely, rosiglitazone treatment actually exacerbates liver steatosis in obese mice that have a higher level of PPAR-γ. Mechanistic studies show that an elevated hepatic PPAR-γ level is associated with an increased expression of genes responsible for lipid metabolism in the liver, particularly Cd36, Fabp4, and Mgat1. The concurrent transfer of these three genes into the mouse liver fully recapitulates the phenotypic change induced by the overexpression of PPAR-γ. These results provide evidence in support of the importance of PPAR-γ in the liver when rosiglitazone is considered for the treatment of fatty liver disease. Clinically, our results suggest the necessity of verifying PPAR-γ levels in the liver when rosiglitazone is considered as a treatment option, and indicate that the direct use of rosiglitazone for treatment of nonalcoholic fatty liver may not be desirable when the patient's PPAR-γ level in the liver is significantly elevated.

Building and Applying Quantitative Adverse Outcome Pathway Models for Chemical Hazard and Risk Assessment

“…Activation of PPAR-γ ultimately results in an increase in the probability of steatosis activation, despite activation of PPAR-α by PFOA, which would normally inhibit steatosis. This result is consistent with observations of increased steatosis in clinical studies of rosiglitazone in obese patients (Massart 2017) and manifestations of steatosis in mice fed a high-fat diet in combination with rosiglitazone (Gao 2016).…”

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

“…Indeed, PPARα and PPARγ regulate this FFA transporter in a tissue-specific manner 97 . In the liver, hepatic CD36 is increased by activating PPARα using the agonist WY14643 97,98 and overexpressing PPARγ or inducing its activity with rosiglitazone 85,99,100 . Moreover, Zhou et al 100 described that CD36 is also a common target gene for other nuclear receptors: liver X receptor (LXR) and pregnane X receptor (PXR), whose activation induces hepatic steatosis in parallel to CD36 expression in mice.…”

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

“…Reduced hepatic steatosis due to increased FAO in hepatocytes occurs upon PPARα activation in rodent models of NAFLD (90,91), while PPARγ activation in rodents (but not humans) increases liver fat accumulation by enhancing hepatic expression of PPARγ-dependent genes involved in lipogenesis (79,92). Interestingly, hepatic PPARγ expression levels determine liver steatosis: mice with low hepatic PPARγ expression are resistant to diet-induced development of fatty liver when treated with rosiglitazone, whereas liver steatosis is exacerbated in obese mice expressing high hepatic levels of PPARγ (93). In mice, PPARγ expression in liver is regulated by the dimeric AP-1 protein complex, thereby controlling hepatic steatosis (94).…”