Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

Wu, Jing; Zhao, Man; Zheng, Hao; Zhang, Hua; Jiang, Ying

doi:10.1038/aps.2010.110

Cited by 22 publications

(11 citation statements)

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“…Advanced glycation end products (AGEs) and their receptor (RAGE) have also been suggested to contribute to the pathogenesis of NASH in HFD-fed rats [18,19]. Also, oxidative stress has been reported to increase glycated protein levels [20].…”

Section: Resultsmentioning

confidence: 99%

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Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Abdelmegeed

Banerjee

Yoo

et al. 2012

Journal of Hepatology

210

192

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Background & Aims Ethanol-inducible cytochrome P450 2E1 (CYP2E1) activity contributes to oxidative stress. However, CYP2E1 may have an important role in the pathogenesis of high-fat mediated nonalcoholic steatohepatitis (NASH). Thus, the role of CYP2E1 in high-fat mediated NASH development was evaluated. Methods Male wild-type (WT) and Cyp2e1-null mice were fed a low-fat diet (LFD, 10% energy-derived) or high-fat diet (HFD, 60% energy-derived) for 10 weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation. Results Liver histology showed that only WT mice fed a HFD developed NASH despite increased steatosis in both WT and Cyp2e1-null mice fed HFD. Markers of oxidative stress such as elevated CYP2E1 activity and protein amounts, lipid peroxidation, protein carbonylation, nitration, and glycation with increased phospho-JNK were all markedly elevated only in the livers of HFD-fed WT mice. Furthermore, while the levels of inflammation markers osteopontin and F4/80 were higher in HFD-fed WT mice, TNFα and MCP-1 contents were lower compared to the corresponding LFD-fed WT. Finally, only HFD-fed WT mice exhibited increased insulin resistance and impaired glucose tolerance. Conclusions These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation and insulin resistance.

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Section: Resultsmentioning

confidence: 99%

“…Protein glycation and its markers namely AGEs and their receptor RAGE, were reported to increase in rat fed HFD, contributing NASH pathogenesis [18,19]. Based on this information and the fact that liver is the main organ to clear AGEs, it was logical to evaluate protein glycation/glycosylation in the present model.…”

Section: Discussionmentioning

confidence: 99%

Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Abdelmegeed

Banerjee

Yoo

et al. 2012

Journal of Hepatology

210

192

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“…Our results are consistent with a previous study, where Sprague-Dawley rats fed a HFD for 16 wk were treated with pentoxifylline for 4 wk (16 mg/kg per day). The results showed decreased AST levels but not ALT, and improvements in basal glucose but not HOMAIR index [19] . Additionally, in a previous study of Sprague-Dawley fed HFD for 10 wk and treated with pentoxifylline for 6 wk (50 mg/kg per day), hepatic steatosis and plasma levels of TNF-α were reduced [20] .…”

Section: Metabolic and Anthropometric Parameters After Pentoxifyllinementioning

confidence: 89%

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

Acedo¹

2015

WJH

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AIM:To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet (HFD). METHODS:Male swiss mice (6-wk old) were fed a highfat diet (HFD; 60% kcal from fat) or AIN-93 (control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally (100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis (macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in RESULTS:Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor (TNF)-α in liver (156.3 ± 17.2 and 62.6 ± 7.6 pg/mL of TNF-α for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced (23.2 ± 6.9 and 12.1 ± 1.6 U/L for nontreated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-α (106.1 ± 17.6 and 51.1 ± 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6 (340.8 ± 51.3 and 166.6 ± 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin (8.1 ± 0.7 and 23.1 ± 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1 (600.2 ± 32.3 and 1508.6 ± 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-α level in the liver of lean mice also increased (29.6 ± 6.6 and 75.4 ± 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction. CONCLUSION:Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice.

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“…Oxidative/nitrative stress has been reported to cause various post-translational modifications of Cys-residues of cellular proteins [23], [29], [32], which negatively affect physiological functions of some essential proteins, prior to the observation of full-blown liver disease [29]. In addition, AZT-treated mice showed significantly higher levels of hepatic AGEs, which can potently trigger ROS production, as demonstrated in experimental models of NASH [21], [43], [44], as compared to the vehicle-treated control, further confirming higher oxidative stress in AZT-treated animals. Further, Gao et al [45] have shown that production of ROS in AZT-exposed primary cardiomyocytes could be attenuated by using resveratrol, a plant-derived anti-oxidant.…”

Section: Discussionmentioning

confidence: 99%

Zidovudine (AZT) and Hepatic Lipid Accumulation: Implication of Inflammation, Oxidative and Endoplasmic Reticulum Stress Mediators

et al. 2013

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The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2α were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPARα as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid β-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice.

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Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

Cited by 22 publications

References 44 publications

Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

Zidovudine (AZT) and Hepatic Lipid Accumulation: Implication of Inflammation, Oxidative and Endoplasmic Reticulum Stress Mediators

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