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Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1.

Kim CS, Kwon Y, Choe SY, Hong SM, Yoo H, Goto T, Kawada T, Choi HS, Joe Y, Chung HT, Yu R - Nutr Metab (Lond) (2015)

Bottom Line: Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway.Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, University of Ulsan, Ulsan, 680-749 South Korea.

ABSTRACT

Background: Obesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism.

Methods: Male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting.

Results: Quercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.

Conclusion: These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

No MeSH data available.


Related in: MedlinePlus

Effect of quercetin on hepatic lipid accumulation and glucose tolerance in HFD-fed obese mice. C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), an HFD supplemented with 0.05 % quercetin (HF + 0.05 % Que) or 0.1 % quercetin (HFD + 0.1 % Que) for 9 weeks (n = 6 per group). a Liver tissues were collected and their TG content was determined. b Representative images of hematoxylin and eosin stained tissue. Original magnification, 200 ×. c Hepatic TBARS levels as a marker of lipid peroxidation. d Plasma alanine aminotransferase (ALT) levels. Data are mean ± SEM of six mice per group. *p < 0.05, **p < 0.01 versus HFD. e Fasting glucose and insulin levels. f Oral glucose tolerance test. Mice were fasted 12 h before receiving by mouth a 20 % glucose solution at a dose of 2 g/kg, and blood samples were taken at the indicated times. Levels of glucose were measured using the glucometer. Data are mean ± SEM of six mice per group. *p < 0.05, # p < 0.005 versus HFD. g Insulin responses. After fasting 5 h, mice were stimulated with or without insulin for 4 min. Expression of p-Akt, and Akt proteins in the liver, adipose tissue, and skeletal muscle of each mouse (n = 4 per group) were examined by Western blot analysis using the indicated antibodies. Data are mean ± SEM of four mice per group. *p < 0.05 versus HFD
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Fig1: Effect of quercetin on hepatic lipid accumulation and glucose tolerance in HFD-fed obese mice. C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), an HFD supplemented with 0.05 % quercetin (HF + 0.05 % Que) or 0.1 % quercetin (HFD + 0.1 % Que) for 9 weeks (n = 6 per group). a Liver tissues were collected and their TG content was determined. b Representative images of hematoxylin and eosin stained tissue. Original magnification, 200 ×. c Hepatic TBARS levels as a marker of lipid peroxidation. d Plasma alanine aminotransferase (ALT) levels. Data are mean ± SEM of six mice per group. *p < 0.05, **p < 0.01 versus HFD. e Fasting glucose and insulin levels. f Oral glucose tolerance test. Mice were fasted 12 h before receiving by mouth a 20 % glucose solution at a dose of 2 g/kg, and blood samples were taken at the indicated times. Levels of glucose were measured using the glucometer. Data are mean ± SEM of six mice per group. *p < 0.05, # p < 0.005 versus HFD. g Insulin responses. After fasting 5 h, mice were stimulated with or without insulin for 4 min. Expression of p-Akt, and Akt proteins in the liver, adipose tissue, and skeletal muscle of each mouse (n = 4 per group) were examined by Western blot analysis using the indicated antibodies. Data are mean ± SEM of four mice per group. *p < 0.05 versus HFD

Mentions: To examine the effects of quercetin in vivo, we generated obese mice fed an HFD with or without quercetin. Quercetin supplementation significantly reduced hepatic triglyceride concentration in the liver of the HFD-fed obese mice (Fig. 1a). In agreement with this, lipid deposition in the liver revealed by histochemical analysis was reduced (Fig. 1b). Quercetin also significantly reduced TBARS levels, a marker of lipid peroxidation (Fig. 1c), and ALT levels, a marker of liver damage (Fig. 1d). We further examined whether the metabolic improvement in response to quercetin observed in the livers of the obese mice reduced obesity-induced glucose intolerance. Levels of fasting glucose and insulin were significantly lower by quercetin (Fig.1e). Glucose tolerance tests confirmed that the quercetin-fed obese mice were more glucose tolerant (Fig. 1f), and activation of the insulin signaling molecules Akt in liver, muscle, and adipose tissue was stimulated (Fig. 1g). Quercetin did not alter food intake, and the HFD-fed mice supplemented with quercetin had a tendency to gain less weight than the control HFD-fed mice (data not shown), as previously reported [16], indicating that the observed benefits of quercetin supplementation are probably associated with the metabolic effects of quercetin.Fig. 1


Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1.

Kim CS, Kwon Y, Choe SY, Hong SM, Yoo H, Goto T, Kawada T, Choi HS, Joe Y, Chung HT, Yu R - Nutr Metab (Lond) (2015)

Effect of quercetin on hepatic lipid accumulation and glucose tolerance in HFD-fed obese mice. C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), an HFD supplemented with 0.05 % quercetin (HF + 0.05 % Que) or 0.1 % quercetin (HFD + 0.1 % Que) for 9 weeks (n = 6 per group). a Liver tissues were collected and their TG content was determined. b Representative images of hematoxylin and eosin stained tissue. Original magnification, 200 ×. c Hepatic TBARS levels as a marker of lipid peroxidation. d Plasma alanine aminotransferase (ALT) levels. Data are mean ± SEM of six mice per group. *p < 0.05, **p < 0.01 versus HFD. e Fasting glucose and insulin levels. f Oral glucose tolerance test. Mice were fasted 12 h before receiving by mouth a 20 % glucose solution at a dose of 2 g/kg, and blood samples were taken at the indicated times. Levels of glucose were measured using the glucometer. Data are mean ± SEM of six mice per group. *p < 0.05, # p < 0.005 versus HFD. g Insulin responses. After fasting 5 h, mice were stimulated with or without insulin for 4 min. Expression of p-Akt, and Akt proteins in the liver, adipose tissue, and skeletal muscle of each mouse (n = 4 per group) were examined by Western blot analysis using the indicated antibodies. Data are mean ± SEM of four mice per group. *p < 0.05 versus HFD
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Effect of quercetin on hepatic lipid accumulation and glucose tolerance in HFD-fed obese mice. C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), an HFD supplemented with 0.05 % quercetin (HF + 0.05 % Que) or 0.1 % quercetin (HFD + 0.1 % Que) for 9 weeks (n = 6 per group). a Liver tissues were collected and their TG content was determined. b Representative images of hematoxylin and eosin stained tissue. Original magnification, 200 ×. c Hepatic TBARS levels as a marker of lipid peroxidation. d Plasma alanine aminotransferase (ALT) levels. Data are mean ± SEM of six mice per group. *p < 0.05, **p < 0.01 versus HFD. e Fasting glucose and insulin levels. f Oral glucose tolerance test. Mice were fasted 12 h before receiving by mouth a 20 % glucose solution at a dose of 2 g/kg, and blood samples were taken at the indicated times. Levels of glucose were measured using the glucometer. Data are mean ± SEM of six mice per group. *p < 0.05, # p < 0.005 versus HFD. g Insulin responses. After fasting 5 h, mice were stimulated with or without insulin for 4 min. Expression of p-Akt, and Akt proteins in the liver, adipose tissue, and skeletal muscle of each mouse (n = 4 per group) were examined by Western blot analysis using the indicated antibodies. Data are mean ± SEM of four mice per group. *p < 0.05 versus HFD
Mentions: To examine the effects of quercetin in vivo, we generated obese mice fed an HFD with or without quercetin. Quercetin supplementation significantly reduced hepatic triglyceride concentration in the liver of the HFD-fed obese mice (Fig. 1a). In agreement with this, lipid deposition in the liver revealed by histochemical analysis was reduced (Fig. 1b). Quercetin also significantly reduced TBARS levels, a marker of lipid peroxidation (Fig. 1c), and ALT levels, a marker of liver damage (Fig. 1d). We further examined whether the metabolic improvement in response to quercetin observed in the livers of the obese mice reduced obesity-induced glucose intolerance. Levels of fasting glucose and insulin were significantly lower by quercetin (Fig.1e). Glucose tolerance tests confirmed that the quercetin-fed obese mice were more glucose tolerant (Fig. 1f), and activation of the insulin signaling molecules Akt in liver, muscle, and adipose tissue was stimulated (Fig. 1g). Quercetin did not alter food intake, and the HFD-fed mice supplemented with quercetin had a tendency to gain less weight than the control HFD-fed mice (data not shown), as previously reported [16], indicating that the observed benefits of quercetin supplementation are probably associated with the metabolic effects of quercetin.Fig. 1

Bottom Line: Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway.Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, University of Ulsan, Ulsan, 680-749 South Korea.

ABSTRACT

Background: Obesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism.

Methods: Male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting.

Results: Quercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.

Conclusion: These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

No MeSH data available.


Related in: MedlinePlus