Short-Term Therapy With Peroxisome Proliferation-Activator Receptor-α Agonist Wy-14,643 Protects Murine Fatty Liver Against Ischemia–Reperfusion Injury

Teoh, Narci C.; Williams, Jacqueline; Hartley, Jennifer; Yu, Jun; McCuskey, Robert S.; Farrell, Geoffrey C.

doi:10.1002/hep.23420

Cited by 27 publications

(50 citation statements)

References 45 publications

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confidence: 99%

“…However, it has been shown that PPAR␣ agonist treatment decreases nonalcoholic steatohepatitis (NASH) development in wild-type mice fed a methionine choline-deficient diet 3,4 and apolipoprotein E2 knock-in (apoE2-KI) mice or foz/foz mice fed a high-fat diet. 5,6 Moreover, PPAR␣ is expressed in many cell types found in the atherosclerotic lesion, such as macrophages, endothelial cells, and smooth muscle cells. 7 In vitro and in vivo studies have suggested that fibrates could exert antiatherogenic actions by improving lipid abnormalities or by modulating several steps of atherogenesis, such as decreasing inflammation and thrombosis, directly in the vascular wall.…”

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confidence: 99%

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Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Lalloyer

Wouters

Baron

et al. 2011

ATVB

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Objective-Peroxisome proliferator-activated receptor-␣ (PPAR␣) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR␣ is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPAR␣ agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPAR␣ therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo-and heterozygous PPAR␣-deficient mice, the consequences of quantitative variations of PPAR␣ gene levels and their response to the synthetic PPAR␣ agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. Methods and Results-Wild-type (ϩ/ϩ), heterozygous (ϩ/Ϫ), and homozygous (Ϫ/Ϫ) PPAR␣-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPAR␣Ϫ/Ϫ apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPAR␣ϩ/ϩ and PPAR␣ϩ/Ϫ apoE2-KI mice, indicating a role of PPAR␣ in liver protection. Moreover, PPAR␣ expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPAR␣ϩ/ϩ and PPAR␣ϩ/Ϫ apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPAR␣ gene were required. Surprisingly, atherosclerosis development was not significantly different among PPAR␣ϩ/ϩ, PPAR␣ϩ/Ϫ, and PPAR␣Ϫ/Ϫ apoE2-KI mice. However, PPAR␣ gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. Key Words: Atherosclerosis Ⅲ PPAR␣ Ⅲ fatty liver disease Ⅲ inflammation Ⅲ murine model F ibrates are lipid-lowering drugs widely used in clinical practice to treat dyslipidemia. 1 Studies performed in peroxisome proliferator-activated receptor-␣ (PPAR␣)-deficient mice have demonstrated that the hypolipidemic effects of fibrates are due to activation of PPAR␣, a ligand-activated transcription factor that modulates lipid metabolism. 2 PPAR␣ is expressed in many tissues, particularly in tissues with high fatty acid oxidation rates, such as liver, kidney, heart, and muscle. After activation by fibrates, PPAR␣ binds as a heterodimer with the retinoid X receptor to PPAR response elements in the promoters of genes implicated in lipid and lipoprotein metabolism. In addition to its effects on lipid metabolism, PPAR␣ also inhibits proinflammatory pathways by negatively interfering with other signaling pathways, such as nuclear factor-B, signal transducer and activator of transcription, or activator protein-1. Consequently, through its effects on lipid metabolism and inflammation, PPAR␣ may modulate pathophysiological pathways implicated in fatty liver disease and atherosclerosis. Data concerning the implicat...

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confidence: 99%

Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Lalloyer

Wouters

Baron

et al. 2011

ATVB

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“…There are some studies showing the detrimental effects of PPARa deficiency or the protective effects of PPARa activation in hepatic ischemia/reperfusion injury models using both lean and steatotic livers [27][28][29][30]. Notably, these models in general produced a more severe injury than our transplantation model and the protection by PPARa likely related to down-regulation of the pro-inflammatory response.…”

Section: Discussionmentioning

confidence: 73%

PPARα is down-regulated following liver transplantation in mice

Nakagawa

Tanaka

Sugioka

et al. 2012

Journal of Hepatology

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“…Sosnowski P et al [8] observed an increase in both ALT activity and liver tissues free radicals level after hind limb IR in rats. Teoh NC et al [9] observed ALT levels release exacerbation 24hours after induced steatohepatitis or simple steatosis hepatic IR in foz/foz mice than wild-type littermates. Ikeda A et al [10] found serum ALT levels significantly less in rat pre-transplanted liver grafts preserved in the University of Wisconsin (UW) solution containing 5% CO (CO-UW solution) group for 21 hours, than preserved in the control UW group one in Lewis rats.…”

Section: Discussionmentioning

confidence: 99%

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2017

JAPLR

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The possible recessing capacity of the antioxidant drug "U-74389g" was studied in a rat model. It included the evaluation of the mean alanine aminotransferase (ALT) levels after induced liver ischemia-reperfusion (IR) injury. The 40 used rats were classified at 2 evaluation endpoints: one of 60 min for groups A and C and one of 120 min for groups B and D after reperfusion. The U-74389g was administered only in groups C and D. The U-74389g administration non-significantly suppressed the ALT levels (p=0.4168). The reperfusion time kept non-significantly elevated the ALT levels (p=0.1309). However, the interaction of U-74389g administration and reperfusion time non-significantly suppressed the ALT levels (p=0.4527). The U-74389g administration non-significantly restored the ALT levels, getting on declining them from significant level to non-significant one.

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Short-Term Therapy With Peroxisome Proliferation-Activator Receptor-α Agonist Wy-14,643 Protects Murine Fatty Liver Against Ischemia–Reperfusion Injury

Abstract: Steatosis increases operative morbidity/mortality from ischemia-reperfusion injury (IRI);

Cited by 27 publications

References 45 publications

Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

PPARα is down-regulated following liver transplantation in mice

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