Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice

Nunes, Patrícia M.; Wright, Alan J.; Veltien, Andor; Asten, Jack J.A. van; Tack, Cees J.; Jones, John G.; Heerschap, Arend

doi:10.1096/fj.13-241208

Cited by 26 publications

(31 citation statements)

References 41 publications

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“…Our hepatic gene expression analysis showed that HFD lowered the mRNA levels of PCSK9 and other SREBP2-target genes (HMGCR, SREBP2), while increasing SREBP1c gene expression in hamster liver. The inducing effect of HFD on transcription of lipogenic genes through activation of SREBP1c has been reported in other animal studies [14,18], our current study further linked fructose diet to deregulated SREBP2 pathway in hamsters. In mice, we did not observe elevated hepatic SPREBP1c mRNA levels in HFD group.…”

Section: Discussionsupporting

confidence: 82%

High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels

et al. 2015

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Background High fructose diet (HFD) induces dyslipidemia and insulin resistance in experimental animals and humans with incomplete mechanistic understanding. By utilizing mice and hamsters as in vivo models, we investigated whether high fructose consumption affects serum PCSK9 and liver LDL receptor (LDLR) protein levels. Results Feeding mice with a HFD increased serum cholesterol and reduced serum PCSK9 levels as compared with the mice fed a normal chow diet (NCD). In contrast to the inverse relationship in mice, serum PCSK9 and cholesterol levels were co-elevated in HFD-fed hamsters. Liver tissue analysis revealed that PCSK9 mRNA and protein levels were both reduced in mice and hamsters by HFD feeding, however, liver LDLR protein levels were markedly reduced by HFD in hamsters but not in mice. We further showed that circulating PCSK9 clearance rates were significantly lower in hamsters fed a HFD as compared with the hamsters fed NCD, providing additional evidence for the reduced hepatic LDLR function by HFD consumption. The majority of PCSK9 in hamster serum was detected as a 53 kDa N-terminus cleaved protein. By conducting in vitro studies, we demonstrate that this 53 kDa truncated hamster PCSK9 is functionally active in promoting hepatic LDLR degradation. Conclusion Our studies for the first time demonstrate that high fructose consumption increases serum PCSK9 concentrations and reduces liver LDLR protein levels in hyperlipidemic hamsters. The positive correlation between circulating cholesterol and PCSK9 and the reduction of liver LDLR protein in HFD-fed hamsters suggest that hamster is a better animal model than mouse to study the modulation of PCSK9/LDLR pathway by atherogenic diets.

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Section: Discussionsupporting

confidence: 82%

High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels

et al. 2015

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“…This observation is in accordance with previous studies comparing the effects of glucose and fructose on liver lipid accumulation both in rodents [18,46,47] and in humans [48]. …”

Section: Discussionsupporting

confidence: 93%

“…Also in this study, the liver lipid pools became equally 13 C enriched in the glucose- and fructose-fed animals after the ingestion of 13 C-labeled lipids, but no control group fed with normal chow was included. It was furthermore demonstrated that plasma concentrations of apoB48 and apoB100 were similar between the glucose- and fructose fed groups [47]. Together, these results do not support the hypothesis that an increased influx of dietary lipids into the liver causes fructose-induced hepatic lipid accumulation.…”

Section: Discussionmentioning

confidence: 91%

“…However, 4 h after the administration of 13 C-labeled lipids, the hepatic incorporation of the ingested dietary lipids was similar among all diet groups. Nunes et al applied the same MRS-based method to determine dietary lipid uptake in the livers of mice fed with pelleted diets containing 60% glucose or fructose for a period of 8 weeks [47]. Also in this study, the liver lipid pools became equally 13 C enriched in the glucose- and fructose-fed animals after the ingestion of 13 C-labeled lipids, but no control group fed with normal chow was included.…”

Section: Discussionmentioning

confidence: 95%

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An In Vivo Magnetic Resonance Spectroscopy Study of the Effects of Caloric and Non-Caloric Sweeteners on Liver Lipid Metabolism in Rats

et al. 2017

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We aimed to elucidate the effects of caloric and non-caloric sweeteners on liver lipid metabolism in rats using in vivo magnetic resonance spectroscopy (MRS) and to determine their roles in the development of liver steatosis. Wistar rats received normal chow and either normal drinking water, or solutions containing 13% (w/v) glucose, 13% fructose, or 0.4% aspartame. After 7 weeks, in vivo hepatic dietary lipid uptake and de novo lipogenesis were assessed with proton-observed, carbon-13-edited MRS combined with 13C-labeled lipids and 13C-labeled glucose, respectively. The molecular basis of alterations in hepatic liver metabolism was analyzed in detail ex vivo using immunoblotting and targeted quantitative proteomics. Both glucose and fructose feeding increased adiposity, but only fructose induced hepatic lipid accumulation. In vivo MRS showed that this was not caused by increased hepatic uptake of dietary lipids, but could be attributed to an increase in de novo lipogenesis. Stimulation of lipogenesis by fructose was confirmed by a strong upregulation of lipogenic enzymes, which was more potent than with glucose. The non-caloric sweetener aspartame did not significantly affect liver lipid content or metabolism. In conclusion, liquid fructose more severely affected liver lipid metabolism in rats than glucose, while aspartame had no effect.

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“…Other studies have shown that rats fed a fructose-rich diet have increased hepatic triglyceride and cholesterol levels [42], and fructose fed to rodents at supraphysiological doses induced steatosis and steatohepatitis by de novo lipogenesis [43]. Meta-analyses have also suggested that fructose consumption is related to the risk factors for metabolic syndrome, such as increased triglyceride levels, stimulated hepatic de novo lipogenesis, and increased visceral fat [44,45,46,47].…”

Section: Discussionmentioning

confidence: 99%

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

et al. 2017

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Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase γ, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases.

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Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice

Cited by 26 publications

References 41 publications

High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels

High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels

An In Vivo Magnetic Resonance Spectroscopy Study of the Effects of Caloric and Non-Caloric Sweeteners on Liver Lipid Metabolism in Rats

Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats

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