Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice

Ishii, Hajime; Horie, Yasuo; Ohshima, Shigetoshi; Anezaki, Yumiko; Kinoshita, Nobukatsu; Dohmen, Takahiro; Kataoka, Ei; Sato, Wataru; Goto, Takashi; Sasaki, Junko; Sasaki, Takehiko; Watanabe, Sumio; Suzuki, Akira; Ohnishi, Hirohide

doi:10.1016/j.jhep.2008.10.031

Cited by 81 publications

(70 citation statements)

References 43 publications

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“…When phosphatase and tensin homolog-deficient mice were killed at 40 weeks of age [29,30], the steatohepatitis, Mallory-Denk bodies, and sinusoidal fibrosis observed were very similar to the histopathological findings of human NASH [10,11,24]. However, in this mouse model, the characteristic honeycomb fibrosis was not observed at that age.…”

Section: Discussionsupporting

confidence: 55%

Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Kitamori

Naito

Tamada

et al. 2011

Environ Health Prev Med

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Objectives Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. Aim This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Methods Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and highcholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks.

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Section: Discussionsupporting

confidence: 55%

Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Kitamori

Naito

Tamada

et al. 2011

Environ Health Prev Med

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“…80 This finding is confirmed in numerous other studies for both omega-3 mix, and EPA and DHA alone. [76][77][78][81][82][83][84][85] In addition to improvement in hepatic steatosis, ob ⁄ ob mice treated with omega-3s have demonstrated markedly decreased SREBP-1 levels with consequent reduced expression of lipogenic genes such as FAS in the liver. 83 The suppression of SREBP-1 and genes involved in lipid metabolism have been confirmed in other publications.…”

Section: Animal Modelsmentioning

confidence: 99%

“…83 The suppression of SREBP-1 and genes involved in lipid metabolism have been confirmed in other publications. 76,78,81,85 In a further series of experiments using leptin-deficient ob ⁄ ob mice, it has been shown that, in addition to confirming reduced liver triglyceride content with omega-3 supplementation, these animals had lowered plasma alanine aminotransferase (ALT) levels and improved hyperglycaemia and hyperinsulinaemia, in a manner hypothesized to be related to PPARa, although this was not measured. 83 The increase in PPARa in response to omega-3 supplementation was later confirmed elsewhere.…”

Section: Animal Modelsmentioning

confidence: 99%

Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease

Masterton

Plevris

Hayes

2010

Alimentary Pharmacology &Amp; Therapeutics

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“…As expected, SILIPHOS does not prevent MCD-induced modifications on membrane lipid composition; however, we can speculate that treatment with SILIPHOS is also able to limit peroxidative damage of mitochondrial proteins in the presence of an increased susceptibility of mitochondria to oxidative stress as that occurring in the MCD model of NASH. In addition, SILIPHOS partially prevents decreases in eicosapentaenoic and docosahexaenoic acids, which exert anti-inflammatory, immunomodulatory, and metabolic effects (Mori et al, 2003;Ishii et al, 2009). More interestingly, we show that SILIPHOS also limits mitochondrial membrane depletion of arachidonic acid observed in MCD rats in our model and also described in human NASH patients (Puri et al, 2007), supporting the observation that SILIPHOS may also act as an anti-inflammatory product (Trappoliere et al, 2009).…”

Section: Siliphos Prevents Mitochondrial Damage In Nash 929mentioning

confidence: 99%

A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

Serviddio

Bellanti

Giudetti

et al. 2009

J Pharmacol Exp Ther

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Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H 2 O 2 production rate were evaluated in isolated liver mitochondria from rats fed a methionine-and cholinedeficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)-and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H 2 O 2 production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE-and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function.

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Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice

Cited by 81 publications

References 43 publications

Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr

Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease

A Silybin-Phospholipid Complex Prevents Mitochondrial Dysfunction in a Rodent Model of Nonalcoholic Steatohepatitis

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