aleglitazar and Liver-Cirrhosis

Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis.. This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS).. LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study.. This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; PPAR alpha; PPAR gamma; Risk Factors

Recent studies have reported that peroxisome proliferator-activated receptor α (PPARα) agonist decreases intrahepatic resistance, whereas PPARγ agonist reduces portosystemic shunts (PSSs) and splanchnic angiogenesis in cirrhotic rats. The present study investigated the effects of a 21-day treatment with the dual PPARα/γ agonist aleglitazar (Ale) on progressive abnormalities in bile-duct-ligated and thioacetamide-induced cirrhotic rats with portal hypertension (PH). In vivo and in vitro effects were evaluated. Chronic Ale treatment significantly up-regulated PPARα/PPARγ receptors and down-regulated tumor necrosis factor-α (TNF-α) and NF-κB expression in the liver, splanchnic tissues, collateral vessels, and intestines of cirrhotic rats with PH. Notably, Ale improved PH by the suppression of systemic/tissue inflammation, hepatic fibrosis, hepatic Rho-kinase-mediated endothelin-1 hyperresponsiveness, intrahepatic/mesenteric angiogenesis, vascular endothelial growth factor expression, PSS, intestinal mucosal injury, and hyperpermeability in cirrhotic rats. Acute Ale treatment inhibited TNF-α-enhanced endothelin-1-induced contraction of primary hepatic stellate cells, vascular endothelial growth factor-induced migration/angiogenesis of liver sinusoidal endothelial cells, and TNF-α-induced disruption of Caco-2 cell monolayer-epithelial barrier. The present study suggested that Ale can potentially treat relevant abnormalities through the inhibition of inflammatory, vasoconstrictive, angiogenic, and mucosal-disrupted pathogenic markers in cirrhosis. Overall, chronic Ale treatment ameliorated PH syndrome by the suppression of hepatic fibrogenesis, neoangiogenesis, vasoconstrictor hyperresponsiveness, splanchnic vasodilatation, and PSS; and decreased intestinal mucosal injury and hyperpermeability in cirrhotic rats.

Topics: Animals; Caco-2 Cells; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Neovascularization, Pathologic; Oxazoles; PPAR alpha; PPAR gamma; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Thiophenes