Beneficial Effects of the Peroxisome Proliferator-Activated Receptor α/γ Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension

Hung Cheng Tsai, Tzu Hao Li, Chia Chang Huang, Shiang Fen Huang, Ren Shyan Liu, Ying Ying Yang*, Yun Cheng Hsieh, Kuei Chuan Lee, Yi Hsiang Huang, Ming Chih Hou, Han Chieh Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1608-1624
Number of pages17
JournalAmerican Journal of Pathology
Volume188
Issue number7
DOIs
StatePublished - Jul 2018

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