Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat

Tanoue, Shirou; Uto, Hirofumi; Kumamoto, Ryo; Arima, Shiho; Hashimoto, Shinichi; Nasu, Yuichiro; Takami, Yoichiro; Moriuchi, Akihiro; Sakiyama, Toshio; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

doi:10.1016/j.bbrc.2011.02.131

Cited by 30 publications

(36 citation statements)

References 30 publications

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“…We previously suggested that the pathophysiology of fatty liver disease may be determined by its etiology, rather than by its severity [14]. The severity of hepatic steatosis induced by a high-fructose diet is milder than that induced by a high-fat diet.…”

Section: Introductionmentioning

confidence: 99%

Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat

et al. 2013

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BackgroundNonalcoholic fatty liver disease (NAFLD) is a risk for hepatocellular carcinoma (HCC), but the association between a high-fructose diet and HCC is not fully understood. In this study, we investigated whether a high-fructose diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN).MethodsSeven-week-old male Sprague–Dawley rats were fed standard chow (controls), a high-fat diet (54% fat), or a high-fructose diet (66% fructose) for 8 weeks. All rats were given DEN at 50 μg/L in drinking water during the same period. Precancerous hepatocytes were detected by immunostaining of the placental form of glutathione-S-transferase (GST-P). The number of GST-P-positive hepatocytes was assessed in liver specimens.ResultsSerum levels of total cholesterol were similar among the three groups, but serum triglyceride, fasting blood glucose, and insulin levels were higher in the high-fructose group compared to the high-fat group. In contrast, hepatic steatosis was more severe in the high-fat group compared with the high-fructose and control groups, but the incidence of GST-P-positive specimens was significantly higher in the high-fructose group compared to the other two groups. The average number of GST-P-positive hepatocytes in GST-P positive specimens in the high-fructose group was also higher than those in the other two groups. This high prevalence of GST-P-positive hepatocytes was accompanied by higher levels of 8-hydroxydeoxyguanosine in serum and liver tissue.ConclusionsThese results indicate that dietary fructose, rather than dietary fat, increases the incidence of precancerous hepatocytes induced by administration of DEN via insulin resistance and oxidative stress in rat. Thus, excessive fructose intake may be a potential risk factor for hepatocarcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat

et al. 2013

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“…In the steatotic liver, impairment of signaling mechanisms due to adaptation to chronic metabolic abnormalities and decreased adenosine triphosphate (ATP) production has been reported to be the likely cause of increased mortality and impaired regeneration after PH (24,33,35). In addition, hepatic steatosis is considered to reduce tolerance to ischemic injury and oxidative stress (OS) (2,33).…”

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confidence: 99%

p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model

Haga

Ozawa²,

Yamada³

et al. 2014

Antioxidants & Redox Signaling

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Aims: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy. Results: Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/ MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration. Innovation: This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms. Conclusion: In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt, caused posthepatectomy necrotic/apoptotic liver injury and delayed regeneration, both mainly via a redox-dependent mechanism. Antioxid. Redox Signal. 21, 2515-2530.

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“…Mice and rats fed with a high-fat diet have shown impaired ability to regenerate liver on partial hepatectomy as compared with animals fed with a normal diet (29,161). Notably, liver regenerative ability of high-fat diet animals or old mice hepatocyte proliferation are inversely correlated with hepatic HDAC1 protein levels (161,173). Similarly, it has been FIG.…”

Section: Metabolites and Dietmentioning

confidence: 90%

“…The liver is a center of energy metabolism and the principal site of detoxification within the body; therefore, detrimental effects induced by an unhealthy diet can usually be observed in this organ for failure of correct tissue regeneration on partial hepatectomy (116). Mice and rats fed with a high-fat diet have shown impaired ability to regenerate liver on partial hepatectomy as compared with animals fed with a normal diet (29,161). Notably, liver regenerative ability of high-fat diet animals or old mice hepatocyte proliferation are inversely correlated with hepatic HDAC1 protein levels (161,173).…”

Section: Metabolites and Dietmentioning

confidence: 95%

New Insights into the Connection Between Histone Deacetylases, Cell Metabolism, and Cancer

Chiaradonna

Cirulli

Palorini

et al. 2015

Antioxidants & Redox Signaling

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Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat

Cited by 30 publications

References 30 publications

Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat

Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat

p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model

New Insights into the Connection Between Histone Deacetylases, Cell Metabolism, and Cancer

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