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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 hepatic lipogenesis and FFA levels.(A) Oil Red O staining of lipids in liver and quantitative analysis of different groups, magnifications: 40X (n = 4). A representative section for each group is shown; (B) Hepatic FFA levels. (C) Elvol6 and Srebp-1c mRNA levels measured by RT-PCR and (D) ACC and SCD-1 mRNA expressions measured by RT-PCR. 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.g004: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on hepatic lipogenesis and FFA levels.(A) Oil Red O staining of lipids in liver and quantitative analysis of different groups, magnifications: 40X (n = 4). A representative section for each group is shown; (B) Hepatic FFA levels. (C) Elvol6 and Srebp-1c mRNA levels measured by RT-PCR and (D) ACC and SCD-1 mRNA expressions measured by RT-PCR. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.

Mentions: As shown in Fig 4A, mice fed a HFr diet have significantly (p<0.05) more lipid accumulation in liver compared to the mice fed a normal chow diet. Oil red O staining of liver from mice fed a HFr diet showed that CoPP decreased lipid accumulation. The decrease in lipid accumulation in mice treated with CoPP was reversed by co-administration of SnMP (Fig 4A). Further our results showed that hepatic FFA levels were significantly increased in mice fed a HFr diet as compared to the control mice. CoPP decreased FFA levels in hepatic tissue as compared to mice fed a fructose diet (Fig 4B; p<0.05). Expression of genes involved in hepatic fatty acid synthesis; Elvol6 and Srebp-1c were induced in mice fed with a high-fructose diet compared to control group. Administration of CoPP significantly reduced the increased mRNA expressions to near control levels (Fig 4C). Similarly, ACC and SCD-1 mRNA expressions were significantly increased in mice fed a HFr diet as compared to the control mice and this increase was negated by treatment with CoPP (Fig 4D). Furthermore, SnMP reversed the beneficial effect of CoPP and decreased ACC and SCD-1 levels in hepatic tissue (p<0.01).


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 hepatic lipogenesis and FFA levels.(A) Oil Red O staining of lipids in liver and quantitative analysis of different groups, magnifications: 40X (n = 4). A representative section for each group is shown; (B) Hepatic FFA levels. (C) Elvol6 and Srebp-1c mRNA levels measured by RT-PCR and (D) ACC and SCD-1 mRNA expressions measured by RT-PCR. 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

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

pone.0128648.g004: Effect of induction of HO-1 (CoPP) and inhibition of HO (SnMP) in mice fed a high fructose diet for 8 weeks on hepatic lipogenesis and FFA levels.(A) Oil Red O staining of lipids in liver and quantitative analysis of different groups, magnifications: 40X (n = 4). A representative section for each group is shown; (B) Hepatic FFA levels. (C) Elvol6 and Srebp-1c mRNA levels measured by RT-PCR and (D) ACC and SCD-1 mRNA expressions measured by RT-PCR. Results are mean±SE, n = 6/group. * p<0.05 vs CTR; # p<0.05 vs HFr, + p<0.05 vs HFr+CoPP.
Mentions: As shown in Fig 4A, mice fed a HFr diet have significantly (p<0.05) more lipid accumulation in liver compared to the mice fed a normal chow diet. Oil red O staining of liver from mice fed a HFr diet showed that CoPP decreased lipid accumulation. The decrease in lipid accumulation in mice treated with CoPP was reversed by co-administration of SnMP (Fig 4A). Further our results showed that hepatic FFA levels were significantly increased in mice fed a HFr diet as compared to the control mice. CoPP decreased FFA levels in hepatic tissue as compared to mice fed a fructose diet (Fig 4B; p<0.05). Expression of genes involved in hepatic fatty acid synthesis; Elvol6 and Srebp-1c were induced in mice fed with a high-fructose diet compared to control group. Administration of CoPP significantly reduced the increased mRNA expressions to near control levels (Fig 4C). Similarly, ACC and SCD-1 mRNA expressions were significantly increased in mice fed a HFr diet as compared to the control mice and this increase was negated by treatment with CoPP (Fig 4D). Furthermore, SnMP reversed the beneficial effect of CoPP and decreased ACC and SCD-1 levels in hepatic tissue (p<0.01).

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