Seladelpar combined with complementary therapies improves fibrosis, inflammation and liver injury in a mouse model of nonalcoholic steatohepatitis

Am J Physiol Gastrointest Liver Physiol. 2023 Nov 28. doi: 10.1152/ajpgi.00158.2023. Online ahead of print.ABSTRACTSeladelpar, a selective PPARδ agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complimentary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high fat Amylin Liver NASH (AMLN) diet were treated for 12 weeks with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis and fibrosis staining) compared to vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and...
Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Source Type: research