It is also possible that intestinal effects of GFT505 contribute to its hepatoprotective role in NAFLD/NASH. Indeed, PPAR-α activation in the intestine by agonists such as GFT505 has recently been shown to contribute to increased HDL production,[31] indicating a potential role for intestinal PPAR-α in the regulation of whole-body lipoprotein BEZ235 molecular weight metabolism. In view of its extensive enterohepatic cycling, GFT505 activation of PPARs in both the intestine and liver thus results in an improved lipid profile that would be beneficial in dyslipidemic NASH patients. The PPARs have

been proposed as targets of interest to treat NAFLD/NASH.[10] Pilot studies with the thiazolidinediones in patients with NASH demonstrated improvements of IR, liver enzymes, and liver fat, but variable results on histological NASH features such as cellular injury, liver inflammation, and fibrosis.[32-35] In two larger studies performed in patients with biopsy-proven NASH, long-term treatment with pioglitazone led to clear

metabolic and liver histological improvement, but did not significantly improve fibrosis.[36, 37] Human studies performed with marketed PPAR-α agonists have generated inconsistent results on NAFLD/NASH. In a prospective study in patients with NASH, gemfibrozil demonstrated favorable effects on liver enzymes,[38] whereas fenofibrate showed variable results.[39-42] No PPAR-δ Ferroptosis assay agonist is clinically available at present. However, treatment of overweight dyslipidemic patients with the PPAR-δ agonist, MBX-8025, for 8 weeks led to a reduction in liver enzymes.[43] Moreover, after 2 weeks of treatment in moderately obese men, the PPAR-δ agonist, GW501516, reduced liver fat content by 20%, in conjunction with see more reductions in plasma GGT levels.[44] To assess the potential

of GFT505 to ameliorate liver dysfunction associated with MetS, its effects on plasma markers of liver dysfunction were evaluated after 4-12 weeks of treatment at 80 mg/day in four independent phase II clinical studies performed in dyslipidemic, prediabetic, insulin-resistant, and/or diabetic patients. Quartile analysis showed that GFT505 significantly lowered liver dysfunction markers, such as ALT, GGT, and ALP. To confirm the therapeutic potential of GFT505 on histological features of NASH, a phase IIb study (ClinicalTrials.gov identifier: NCT01694849) in biopsy-proven NASH patients is currently ongoing. In conclusion, together with its favorable effects on hepatic and peripheral insulin sensitivity, glucose homeostasis, and lipid metabolism,[19, 45] the present study shows the therapeutic potential of GFT505 for NASH treatment. By activating both PPAR-α and PPAR-δ, GFT505 acts on key cellular mechanisms involved in NAFLD/NASH pathogenesis, including TG accumulation, extracellular matrix synthesis, and inflammation.