Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome - PubMed (original) (raw)

Takuji Ishimoto, Nanxing Li, Christina Cicerchi, David J Orlicky, Philip Ruzycki, Christopher Rivard, Shinichiro Inaba, Carlos A Roncal-Jimenez, Elise S Bales, Christine P Diggle, Aruna Asipu, J Mark Petrash, Tomoki Kosugi, Shoichi Maruyama, Laura G Sanchez-Lozada, James L McManaman, David T Bonthron, Yuri Y Sautin, Richard J Johnson

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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

Miguel A Lanaspa et al. Nat Commun. 2013.

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Abstract

Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.

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Figures

Figure 1

Figure 1. Effect of Glucose consumption on Metabolic Parameters in WT and KHK A/C KO Mice

WT mice and KHK-A/C KO mice were provided drinking water containing 10% glucose or tap water with normal mouse chow ad libitum for 14 weeks (n = 6 per group). (a) Cumulative energy intake of glucose water for 14 weeks. (b) Left. Cumulative total energy intake of chow diet with 10% glucose water or tap water for 14 weeks. Right. Total energy intake per gram body weight per day of normal chow diet with 10% glucose water or tap water for 14 weeks. (c) Growth curves of WT mice and KHK-A/C KO mice. Epididymal fat weight (d). Serum insulin (e). HOMA-R (f). Serum leptin (g). Key: HOMA-R, homeostasis model assessment for insulin resistance. Data represent means ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. respective water control. #P < 0.05. ### P < 0.001 (ANOVA, Tukey post hoc test).

Figure 2

Figure 2. Effect of Glucose consumption on Liver histology and function

WT mice and KHK-A/C KO mice were given 10% glucose water, or tap water for 14 weeks with normal chow diet ad libitum (n = 6 per group). (a) Liver weight. (b) Gross images of liver showing increased liver size and pale color in WT but not KHK-A/C KO mice given glucose (size bar: 1 cm). (c) Representative images of oil red O staining demonstrating increased fat accumulation (red) in WT but not KHK-A/C KO mice given glucose. (size bar 50 µM) (d) Representative images of H and E staining showing areas of macrosteatosis (white vesicles) in zone 2 and microsteatosis in zone 1 (surrounding the central vein, CV) in WT but not KHK-A/C KO mice given glucose, PT: Portal Triad. (e) Intrahepatic triglyceride levels. (size bar 50 µM) (f) Intrahepatic cholesterol levels. (g) Serum aspartate aminotransferase (AST) levels. (h) Serum alanine aminotransferase (ALT) levels. Data represent means ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. respective water control. #P < 0.05. ##P < 0.01. ### P < 0.001. (ANOVA, Tukey post hoc)

Figure 3

Figure 3. Effect of Glucose consumption on Liver enzymes

(a, b) Western blot of ATP citrate lyase (ACL, a) and fatty acid synthase (FAS, b). Relative intensity to β-actin in liver (n = 5), (full length image of representative western blot in Supplementary Fig S5). (c) Serum β-hydroxy butyrate concentration (n = 6). (d) Hepatic Fructose content. (e) Hepatic sorbitol content. (f) Serum fructose concentration. (g–i) Western blot analysis of aldose reductase (AR, g), KHK (h) and sorbitol dehydrogenase (SDH, i). Relative intensity to to β-actin in liver (n = 5).), (full length image of representative western blot in supplementary Fig S5). Data represent means ± s.e.m. *P < 0.05, **P < 0.01 vs. respective water control. (ANOVA, Tukey post hoc) a, P < 0.05 vs WT water by t-test.

Figure 4

Figure 4. Aldose reductase knockout mice do not develop glucose-induced fatty liver

WT mice and aldose reductase knockout mice (AR KO) given ad libitum normal chow diet with 10% glucose water, or tap water for 14 weeks (n = 3–4). (a) Cumulative total energy intake of chow diet with 10% glucose water or tap water for 14 weeks. (b) Growth curves of WT mice and AR KO mice. (c) Liver weight. (d) Hepatic sorbitol content. (e) Hepatic fructose content. (f) Intrahepatic triglyceride levels. (g) Serum aspartate aminotransferase (AST) levels. (h) Serum alanine aminotransferase (ALT) levels. Data represent means ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001 vs. respective water control. #P < 0.05. ##P < 0.01. ### P < 0.001.(ANOVA, Tukey post hoc)

Figure 5

Figure 5. Analysis of Mice Matched for GLucose and Total Energy Intake

WT mice and KHK-A/C KO mice were give 10% glucose water for 14 weeks with normal chow diet ad libitum (n = 4 per group. (n = 4 per group). (a) Cumulative glucose intake (n = 4). (a) Cumulative total energy intake (n = 4). (c) Intrahepatic triglyceride levels (n = 4). (d) Quantification of oil red O staining (n = 4). (e) Serum aspartate aminotransferase (AST) levels (n = 4). (f) Serum insulin levels (n = 4). Data represent means ± s.e.m. *P < 0.05, **P < 0.01 by t-test. N.S., not significant.(ANOVA Tukey post hoc analysis)

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References

    1. Atkins R. Dr. Atkins’ New Diet Revolution. Avon Books; 1998.
    1. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, Ludwig DS. Effects of a low-glycemic load vs low-fat diet in obese young adults: a randomized trial. Jama. 2007;297:2092–2102. - PubMed
    1. Gardner CD, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007;297:969–977. - PubMed
    1. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293:43–53. - PubMed
    1. Foster GD, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Annals of internal medicine. 2010;153:147–157. - PMC - PubMed

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