RT Journal Article SR Electronic T1 PBI-4050 reduces stellate cell activation and liver fibrosis through modulation of intracellular ATP levels and LKB1-AMPK-mTOR pathway JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.118.250068 DO 10.1124/jpet.118.250068 A1 Brigitte Grouix A1 Francois Sarra-Bournet A1 Martin Leduc A1 Jean-Christophe Simard A1 Kathy Hince A1 Lilianne Geerts A1 Alexandra Blais A1 Liette Gervais A1 Alexandre Laverdure A1 Alexandra Felton A1 Jonathan Richard A1 Jugurtha Ouboudinar A1 William Gagnon A1 Francois Leblond A1 Pierre Laurin A1 Lyne Gagnon YR 2018 UL http://jpet.aspetjournals.org/content/early/2018/08/09/jpet.118.250068.abstract AB Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We have previously shown that PBI-4050 is a dual GPR40 agonist/GPR84 antagonist exerting anti-fibrotic, anti-inflammatory and anti-proliferative actions. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The anti-fibrotic effect of PBI-4050 was evaluated in carbon tetrachloride and in bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl4-induced serum aspartate aminotransferase level, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail and multiple pro-fibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl4-induced injury, while restoring PPARγ to the control level. In a bile duct ligation rat model, collagen deposition and α-SMA protein level were also attenuated by PBI-4050 treatment. TGF-β-activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited the proliferation of HSCs by arresting the cells in a G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through reduction of intracellular ATP levels, activation of LKB1 and AMPK, and blocking of mTOR, resulting in reduced protein and mRNA levels of α-SMA and CTGF, and restoration of PPARγ mRNA expression. Our findings suggest that PBI-4050 may exert its anti-fibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and LKB1-AMPK-mTOR pathway in stellate cells and suggests that PBI-4050 may be a promising agent for treating liver fibrosis.