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Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.

Sodhi K, Puri N, Favero G, Stevens S, Meadows C, Abraham NG, Rezzani R, Ansinelli H, Lebovics E, Shapiro JI - PLoS ONE (2015)

Bottom Line: Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05).Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose).Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.

ABSTRACT

Background: Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.

Hypothesis: We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.

Methods and results: We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.

Conclusion: Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

No MeSH data available.


Related in: MedlinePlus

Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on HO-1 mRNA, SIRT1 mRNA, plasma isoprostane and gp phox91 protein expression.(A) HO-1 mRNA levels measured by RT-PCR. (B) SIRT1 mRNA levels measured by RT-PCR. (C) Plasma isoprostane levels and (D) gp phox91 protein expression. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
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pone.0128648.g005: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on HO-1 mRNA, SIRT1 mRNA, plasma isoprostane and gp phox91 protein expression.(A) HO-1 mRNA levels measured by RT-PCR. (B) SIRT1 mRNA levels measured by RT-PCR. (C) Plasma isoprostane levels and (D) gp phox91 protein expression. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.

Mentions: Mice fed a HFr diet and concurrently treated with CoPP exhibited increased hepatic HO-1 expression as compared to the control (Fig 5A). SnMP also increased HO-1 expression. However, these findings are not surprising as SnMP, which induced a significant increase in HO-1 expression, remains a potent inhibitor of HO activity, as shown previously [35, 42, 43]. Mice fed a HFr diet exhibited decreased hepatic SIRT1 expression as compared to the control (Fig 5B). Furthermore, SnMP reversed the beneficial effect of CoPP and decreased the expression of SIRT1 (p<0.05). Mice fed a HFr diet had increased plasma isoprostane levels and an increased expression of the hepatic NADPH-oxidase-subcomponent, gp/phox91 (Fig 5C and 5D respectively; p<0.05), a potent marker of oxidative stress, compared to the control mice. CoPP reduced isoprostane and gpphox 91 levels as compared to mice fed a fructose diet (p<0.05). SnMP reversed the effect of CoPP and increased the markers of oxidative stress.


Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.

Sodhi K, Puri N, Favero G, Stevens S, Meadows C, Abraham NG, Rezzani R, Ansinelli H, Lebovics E, Shapiro JI - PLoS ONE (2015)

Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on HO-1 mRNA, SIRT1 mRNA, plasma isoprostane and gp phox91 protein expression.(A) HO-1 mRNA levels measured by RT-PCR. (B) SIRT1 mRNA levels measured by RT-PCR. (C) Plasma isoprostane levels and (D) gp phox91 protein expression. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476565&req=5

pone.0128648.g005: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on HO-1 mRNA, SIRT1 mRNA, plasma isoprostane and gp phox91 protein expression.(A) HO-1 mRNA levels measured by RT-PCR. (B) SIRT1 mRNA levels measured by RT-PCR. (C) Plasma isoprostane levels and (D) gp phox91 protein expression. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
Mentions: Mice fed a HFr diet and concurrently treated with CoPP exhibited increased hepatic HO-1 expression as compared to the control (Fig 5A). SnMP also increased HO-1 expression. However, these findings are not surprising as SnMP, which induced a significant increase in HO-1 expression, remains a potent inhibitor of HO activity, as shown previously [35, 42, 43]. Mice fed a HFr diet exhibited decreased hepatic SIRT1 expression as compared to the control (Fig 5B). Furthermore, SnMP reversed the beneficial effect of CoPP and decreased the expression of SIRT1 (p<0.05). Mice fed a HFr diet had increased plasma isoprostane levels and an increased expression of the hepatic NADPH-oxidase-subcomponent, gp/phox91 (Fig 5C and 5D respectively; p<0.05), a potent marker of oxidative stress, compared to the control mice. CoPP reduced isoprostane and gpphox 91 levels as compared to mice fed a fructose diet (p<0.05). SnMP reversed the effect of CoPP and increased the markers of oxidative stress.

Bottom Line: Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05).Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose).Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.

ABSTRACT

Background: Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.

Hypothesis: We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.

Methods and results: We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.

Conclusion: Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

No MeSH data available.


Related in: MedlinePlus