HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis

Abstract

Objectives Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor d (PPARd) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARd/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD. Methods The methionine-and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088. Key findings Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress. Conclusions These positive results indicated that PPARd/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.

Icariside II Exerts Anti-Type 2 Diabetic Effect by Targeting PPARα/γ: Involvement of ROS/NF-κB/IRS1 Signaling Pathway

“…Thus, the effect of ICS II on lipid metabolism were explored, and we found that ICS II efficiently regulated lipid metabolism and reversed the excessive accumulation of fat in liver of db/db mice. In addition, glucose and lipid abnormalities are important factors, resulting in the progression of β cells dysfunction or pancreatic islets destruction [ 31 , 32 , 33 ]. Our findings indicated that ICS II significantly improved structure of pancreas and restored the numbers of β cells in db/db mice, which further confirmed that ICS II was potently against T2DM, and its possible underlying mechanism is worth investigating in depth.…”