ABSTRACT
IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet; the foz/foz model; the CCl4-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of ß-oxidation-related and fatty acid desaturation-related genes in both the methionine- and choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524-537).
ABSTRACT
CXC-chemokine receptors 1 and 2 and their ligands (CXCL1, 2, 3, 5, 6, 7, and 8) induce the selective recruitment of neutrophils during inflammation. Such receptors have not been characterized yet in guinea pig, an animal inflammation model of interest. We report the identification, cloning, and characterization of a CXCL8 receptor in guinea pig. Human CXCL8 produced in vivo neutrophilia, chemotaxis and intracellular calcium release of guinea pig neutrophils. The expression of this receptor at their neutrophil surface was investigated. The cDNA encoding a functional CXCL8 receptor was cloned from guinea pig neutrophils and sequenced. It was synthesized using RT-PCR, with oligonucleotide primers derived from well conserved regions of published CXCL8 receptors. This sequence presented an open reading frame coding for 352 amino acids and shares, at the amino acid level, 70 and 69% identity with human and rabbit CXCR2, respectively. The receptor was mainly expressed in neutrophils but it was also present in kidney, lung, spleen and, to a less extent, in heart. Cloned receptor transfected cells showed that this receptor displayed high affinity for human CXCL8, slightly lower than the affinity observed with guinea pig neutrophils. CXC chemokines from both rabbit and human were shown to induce inositol phosphate accumulation in these transfected cells. Receptor binding and activation characteristics together with sequence homology suggested that we identified a guinea pig equivalent of the human CXCR2 receptor.
