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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 western blot and densitometry analysis of aortic tissue.(A) iNOS protein expression. (B) peNOS protein expression and (C) pAMPK protein expression. Data are shown as mean band density normalized to β-actin. Results are mean±SE, n = 4/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
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pone.0128648.g008: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on western blot and densitometry analysis of aortic tissue.(A) iNOS protein expression. (B) peNOS protein expression and (C) pAMPK protein expression. Data are shown as mean band density normalized to β-actin. Results are mean±SE, n = 4/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.

Mentions: Our results showed activation of inflammatory pathways (iNOS) in the aorta of mice fed a HFr diet (Fig 8A). CoPP increased the aortic expression of peNOS (Fig 8B; p<0.05); the concurrent administration of SnMP with CoPP decreased the expression of peNOS. Therefore CoPP increased NO bioavailability, restoring the balance of aortic eNOS and iNOS isoforms and the redox state. Further mice fed a HFr diet had a decreased expression of pAMPK (Fig 8C; p<0.05) as compared to the control group. CoPP increased pAMPK levels (p <0.05) as compared to mice fed a fructose diet. SnMP abolished the beneficial effects of CoPP.


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 western blot and densitometry analysis of aortic tissue.(A) iNOS protein expression. (B) peNOS protein expression and (C) pAMPK protein expression. Data are shown as mean band density normalized to β-actin. Results are mean±SE, n = 4/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.g008: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on western blot and densitometry analysis of aortic tissue.(A) iNOS protein expression. (B) peNOS protein expression and (C) pAMPK protein expression. Data are shown as mean band density normalized to β-actin. Results are mean±SE, n = 4/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
Mentions: Our results showed activation of inflammatory pathways (iNOS) in the aorta of mice fed a HFr diet (Fig 8A). CoPP increased the aortic expression of peNOS (Fig 8B; p<0.05); the concurrent administration of SnMP with CoPP decreased the expression of peNOS. Therefore CoPP increased NO bioavailability, restoring the balance of aortic eNOS and iNOS isoforms and the redox state. Further mice fed a HFr diet had a decreased expression of pAMPK (Fig 8C; p<0.05) as compared to the control group. CoPP increased pAMPK levels (p <0.05) as compared to mice fed a fructose diet. SnMP abolished the beneficial effects of CoPP.

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