Influence of Fenofibrate Treatment on Triacylglycerides, Diacylglycerides and Fatty Acids in Fructose Fed Rats

Kopf, Thomas; Schaefer, Hans-Ludwig; Troetzmueller, Martin; Koefeler, Harald; Bröenstrup, Mark; Konovalova, Tatiana; Schmitz, Gerd

doi:10.1371/journal.pone.0106849

Cited by 22 publications

(14 citation statements)

References 47 publications

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“…Fenofibrate increased fatty acid oxidation, significantly reduced serum triglyceride and subsequently alleviated PZA‐induced liver injury in rats. These results were consistent with the reports that fenofibrate activated PPARα and increased fatty acid oxidation and reduced liver fat accumulation (Kopf et al , ; Zheng et al , ). In contrast, mice deficient in PPARα and those nullizygous for PPARα both showed a minimal steatotic phenotype under fed conditions but manifested an exaggerated steatotic response to fasting (Reddy, ), revealing that defects in PPARα‐inducible fatty acid oxidation determine the severity of the fatty liver phenotype to conditions reflecting starvation.…”

Section: Discussionsupporting

confidence: 93%

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Zhang

Guo

Hassan

et al. 2016

J of Applied Toxicology

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Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator-activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down-regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co-treatment that acts as a PPARα agonist. In contrast, short-termstarvation significantly aggravated the severity of PZA-induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA-induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA-induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 93%

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Zhang

Guo

Hassan

et al. 2016

J of Applied Toxicology

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“…There is also preclinical evidence to suggest that fructose itself promotes hepatic DAG accumulation. Short-term high-fructose feeding to rodents increased hepatic DAG content [ 140 , 141 , 142 ] and was associated with PKCε activation and impaired insulin signaling [ 78 ]. In addition, fructose activates ChREBP and promotes hepatic gluconeogenesis independently of hepatic insulin signaling, which may contribute to hepatic insulin resistance ( Figure 3 ) [ 58 ].…”

Section: Does Fructose Consumption Cause Disease Progression In Humentioning

confidence: 99%

Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease

Horst¹,

2017

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Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

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“…Elevated fructose consumption is also known to adversely impact whole body glucose tolerance and insulin sensitivity (summarised in 8 ), however the mechanisms responsible for these effects are still not completely understood. While there are some discrepancies between different studies, livers from FR–fed rodents frequently exhibit (1) diacylglycerol (DAG) accumulation 9 10 11 , (2) activation of inflammatory and stress signalling pathways, including activation of c-Jun N-terminal kinases (JNK) and endoplasmic reticulum stress markers 12 13 14 15 16 17 and (3) inhibition of components of the insulin signalling cascade 10 15 17 18 19 .…”

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confidence: 99%

Disparate metabolic response to fructose feeding between different mouse strains

Montgomery

Fiveash

Braude

et al. 2015

Sci Rep

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Diets enriched in fructose (FR) increase lipogenesis in the liver, leading to hepatic lipid accumulation and the development of insulin resistance. Previously, we have shown that in contrast to other mouse strains, BALB/c mice are resistant to high fat diet-induced metabolic deterioration, potentially due to a lack of ectopic lipid accumulation in the liver. In this study we have compared the metabolic response of BALB/c and C57BL/6 (BL6) mice to a fructose-enriched diet. Both strains of mice increased adiposity in response to FR-feeding, while only BL6 mice displayed elevated hepatic triglyceride (TAG) accumulation and glucose intolerance. The lack of hepatic TAG accumulation in BALB/c mice appeared to be linked to an altered balance between lipogenic and lipolytic pathways, while the protection from fructose-induced glucose intolerance in this strain was likely related to low levels of ER stress, a slight elevation in insulin levels and an altered profile of diacylglycerol species in the liver. Collectively these findings highlight the multifactorial nature of metabolic defects that develop in response to changes in the intake of specific nutrients and the divergent response of different mouse strains to dietary challenges.

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Influence of Fenofibrate Treatment on Triacylglycerides, Diacylglycerides and Fatty Acids in Fructose Fed Rats

Cited by 22 publications

References 47 publications

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease

Disparate metabolic response to fructose feeding between different mouse strains

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