Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet

Koppe, Sean; Sahai, Atul; Malladi, Padmini; Whitington, Peter F.; Green, Richard M.

doi:10.1016/j.jhep.2004.06.030

Cited by 113 publications

(93 citation statements)

References 50 publications

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“…We found that PTX treatment ameliorated hepatic function in rats administrated a high-fat diet by alleviating the inflammatory response and decreasing AST and GLU levels. This observation was [10] and an animal model of NASH induced by a diet deficient in methionine and choline [29] , which suggests that PTX protected against high-fat diet-induced NASH in rats. PTX is a phosphodiesterase inhibitor with rheological and vasodilating properties.…”

Section: Discussionmentioning

confidence: 70%

“…Increased expression of TNFα contributes to the development of steatosis, induces inflammatory and fibrogenic responses, and contributes to the progression of NAFLD. In vitro and in vivo studies have shown that PTX suppresses or reduces the production of TNFα, and beneficial effects of PTX have been reported in NASH [10,29] . Our previous study demonstrated that PTX inhibited TNFα expression in the livers of rats with NASH fed a high-fat diet [11] .…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Zheng

et al. 2010

Acta Pharmacol Sin

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Aim:To investigate the expression of advanced glycation end products (AGEs) and their receptor RAGE in the livers and blood vessels of rats with non-alcoholic steatohepatitis (NASH) and the effect of pentoxifylline (PTX) on liver and artery function in rats with NASH. Methods: Sprague-Dawley rats were fed a high-fat diet for 12 weeks and given PTX by gavage for 4 weeks. The effects of PTX on hepatic liver and vessel function as well as the expression of AGE and RAGE in rats with NASH were assessed. The intima-media thickness (IMT) of the aorta and carotid artery was evaluated using ultrasonography. Results: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group. The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group. The IMT was reduced in NASH rats after treatment with PTX. Rats with NASH demonstrated higher AGE and RAGE protein levels in the liver and arteries compared with those of control rats. PTX treatment in NASH rats resulted in a decrease in AGE and RAGE protein levels in the liver and arteries compared with those in the NASH group. Conclusion: Early atherosclerosis was observed in rats with NASH induced by a 16-week high-fat diet. High expression of AGE and RAGE in the livers and arteries of rats with NASH may contribute to the pathogenesis of NASH and early atherosclerosis. PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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

Zhao

Zheng

et al. 2010

Acta Pharmacol Sin

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“…42,45,46 The symptoms found in this model represent lesions of human NASH, but in a noneinsulin-resistant state, although some studies have found hepatic insulin resistance in this model. 47 The results reported here may be the beginning of many future studies involving NADPH oxidase activationeinduced TLR4 trafficking and could be validated using other models of NASH.…”

Section: Discussionmentioning

confidence: 91%

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Das

Alhasson

Dattaroy

et al. 2015

The American Journal of Pathology

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The molecular events that link NADPH oxidase activation and the induction of Toll-like receptor (TLR)-4 recruitment into hepatic lipid rafts in nonalcoholic steatohepatitis (NASH) are unclear. We hypothesized that in liver, NADPH oxidase activation is key in TLR4 recruitment into lipid rafts, which in turn upregulates NF-kB translocation to the nucleus and subsequent DNA binding, leading to NASH progression. Results from confocal microscopy showed that liver from murine and human NASH had NADPH oxidase activation, which led to the formation of highly reactive peroxynitrite, as shown by 3-nitrotyrosine formation in diseased liver. Expression and recruitment of TLR4 into the lipid rafts were significantly greater in rodent and human NASH. The described phenomenon was NADPH oxidase, p47phox, and peroxynitrite dependent, as liver from p47phox-deficient mice and from mice treated with a peroxynitrite decomposition catalyst [iron(III) tetrakis(p-sulfonatophenyl)porphyrin] or a peroxynitrite scavenger (phenylboronic acid) had markedly less Tlr4 recruitment into lipid rafts. Mechanistically, peroxynitrite-induced TLR4 recruitment was linked to increased IL-1b, sinusoidal injury, and Kupffer cell activation while blocking peroxynitrite-attenuated NASH symptoms. The results strongly suggest that NADPH oxidaseemediated peroxynitrite drove TLR4 recruitment into hepatic lipid rafts and inflammation, whereas the in vivo use of the peroxynitrite scavenger phenylboronic acid, a novel synthetic molecule having high reactivity with peroxynitrite, attenuates inflammatory pathogenesis in NASH. (Am J Pathol 2015 http://dx

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“…The by far most often used nutritional model is the methionine-choline deficient diet (MCD) (Weltman et al, 1996). Feeding this diet leads to a rapid development of hepatic steatosis, inflammation and subsequent fibrosis (Koppe et al, 2004), because the secretion of very low density particles (VLDL) is impaired. This model does, however, not sufficiently mimic NASH as seen in patients.…”

Section: I42 Models For Non-alcoholic Steatohepatitis (Nash)mentioning

confidence: 99%

The Role of PI3K p110gamma in chronic liver injury

Dostert¹,

Saugspier²,

Dorn³

et al. 2012

Z Gastroenterol

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Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet

Cited by 113 publications

References 50 publications

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

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

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

The Role of PI3K p110gamma in chronic liver injury

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