Abstract
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.
- amp-dependent protein kinase (AMPK)
- anti-inflammatory drugs
- fibroblasts
- free fatty acid receptors
- g protein-coupled receptors (GPCRS)
- The American Society for Pharmacology and Experimental Therapeutics