The effect of acetylsalicylic acid and pentoxifylline in guinea pigs with non‐alcoholic steatohepatitis

Ipsen, David Højland; Skat-Rørdam, Josephine; Svenningsen, Marianne; Andersen, Mads Varis Nis; Latta, Markus; Buelund, Lene E.; Lintrup, Kristine; Skaarup, René; Lykkesfeldt, Jens; Tveden‐Nyborg, Pernille

doi:10.1111/bcpt.13549

Cited by 9 publications

(22 citation statements)

References 42 publications

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“…In contrast to these findings, we have not previously been able to measure insulin resistance in the guinea pig model for NAFLD/NASH [ 28 , 40 ]. However, the control diet in the study of Podell and coworkers had a lower energy content (10.5 MJ/kg) compared to the LF-HSt (12.6 MJ/kg, Table S1 ) diet used as a control diet for this and previous studies in our group [ 26 , 28 , 29 , 30 , 40 , 51 ]. Considering the lower energy content as well as the higher amount of refined sugar in the high fat diet, the current study explored if insulin resistance could be induced by HFCS supplements in the drinking water while ensuring comparison to a low-calorie low-starch control group (LF-LSt, 11.2 MJ/kg).…”

Section: Discussionmentioning

confidence: 83%

“…Consequently, the starch content of control diets applied in preclinical modeling might induce a metabolic state with little relevance to a healthy human control and—unintentionally—reduce the value of comparisons. For the guinea pig NAFLD/NASH model, a low-fat high-starch (LF-HSt) diet promotes a healthy liver phenotype, however guinea pigs do not display differences in weight or glucose tolerance compared to a HFD [ 26 , 27 , 28 , 29 , 30 ]. To investigate putative differences in a more metabolically relevant control group, a diet low in fat and starch was included (LF-LSt).…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

et al. 2021

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Pharmacological treatment modalities for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are scarce, and discoveries are challenged by lack of predictive animal models adequately reflecting severe human disease stages and co-morbidities such as obesity and type 2 diabetes. To mimic human NAFLD/NASH etiology, many preclinical models rely on specific dietary components, though metabolism may differ considerably between species, potentially affecting outcomes and limiting comparability between studies. Consequently, understanding the physiological effects of dietary components is critical for high translational validity. This study investigated the effects of high fat, cholesterol, and carbohydrate sources on NASH development and metabolic outcomes in guinea pigs. Diet groups (n = 8/group) included: low-fat low-starch (LF-LSt), low-fat high-starch (LF-HSt), high-fat (HF) or HF with 4.2%, or 8.4% sugar water supplementation. The results showed that caloric compensation in HF animals supplied with sugar water led to reduced feed intake and a milder NASH phenotype compared to HF. The HF group displayed advanced NASH, weight gain and glucose intolerance compared to LF-LSt animals, but not LF-HSt, indicating an undesirable effect of starch in the control diet. Our findings support the HF guinea pig as a model of advanced NASH and highlights the importance in considering carbohydrate sources in preclinical studies of NAFLD.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

et al. 2021

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“…Liver sections for histology were fixed in 10% formalin and paraffin embedded prior to slicing in 2–4 µm thick sections and staining with hematoxylin and eosin (H&E) or picrosirius red (PSR) with Weigert’s hematoxylin solution. All histopathological scorings were performed in a randomized and blinded manner, as previously described for the guinea pig model and according to Kleiner et al [ 33 , 35 , 39 , 40 ]. The reliability of scoring was assessed by Cohen’s Kappa index [ 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

Vitamin C Deficiency May Delay Diet-Induced NASH Regression in the Guinea Pig

et al. 2021

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Oxidative stress is directly linked to non-alcoholic fatty liver disease (NAFLD) and the progression to steaotohepatitis (NASH). Thus, a beneficial role of antioxidants in delaying disease progression and/or accelerating recovery may be expected, as corroborated by recommendations of, e.g., vitamin E supplementation to patients. This study investigated the effect of vitamin C deficiency—often resulting from poor diets low in fruits and vegetables and high in fat—combined with/without a change to a low fat diet on NAFLD/NASH phenotype and hepatic transcriptome in the guinea pig NASH model. Vitamin C deficiency per se did not accelerate disease induction. However, the results showed an effect of the diet change on the resolution of hepatic histopathological hallmarks (steatosis, inflammation, and ballooning) (p < 0.05 or less) and indicated a positive effect of a high vitamin C intake when combined with a low fat diet. Our data show that a diet change is important in NASH regression and suggest that a poor vitamin C status delays the reversion towards a healthy hepatic transcriptome and phenotype. In conclusion, the findings support a beneficial role of adequate vitamin C intake in the regression of NASH and may indicate that vitamin C supplementation in addition to lifestyle modifications could accelerate recovery in NASH patients with poor vitamin C status.

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“…Thus, it could be stated that the downregulation of ER stress and related protein expression by PTX can be attributed to its anti-inflammatory effect. However, in a Guinea pig-fed HFD-induced NAFLD model, pentoxifylline treatment for 8 weeks did not reduce steatosis, inflammation, and fibrosis (Ipsen et al, [ 81 ]. Surprisingly, PTX treatment (100 mg/kg) for 4 days/week for three weeks was shown to exacerbate fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis and it was suggested that PTX could aggravate fatty liver in patients with preexisting hyperglycemia (Massart et al, [ 82 ]).…”

Section: Antioxidants In Experimentally Induced Nafldmentioning

confidence: 99%

A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases

Ezhilarasan

Thangavelu

2022

Oxidative Medicine and Cellular Longevity

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Nonalcoholic fatty liver disease (NAFLD) defines fat accumulation in the liver, and it is commonly associated with metabolic syndromes like diabetes and obesity. Progressive NAFLD leads to nonalcoholic steatohepatitis (NASH) and ultimately causes cirrhosis and hepatocellular carcinoma, and NASH is currently a frequent cause of liver transplantation. Oxidative stress is often contributed to the progression of NAFLD, and hence, antioxidants such as silymarin, silybin, or silibinin, pentoxifylline, resveratrol, and vitamins A, C, and E are used in clinical trials against NAFLD. Silymarin induces the peroxisome proliferator-activated receptor α (PPARα), a fatty acid sensor, which promotes the transcription of genes that are required for the enzymes involved in lipid oxidation in hepatocytes. Silybin inhibits sterol regulatory element-binding protein 1 and carbohydrate response element-binding protein to downregulate the expression of genes responsible for de novo lipogenesis by activating AMP-activated protein kinase phosphorylation. Pentoxifylline inhibits TNF-α expression and endoplasmic reticulum stress-mediated inflammatory nuclear factor kappa B (NF-κB) activation. Thus, it prevents NAFLD to NASH progression. Resveratrol inhibits methylation at Nrf-2 promoters and NF-κB activity via SIRT1 activation in NAFLD conditions. However, clinically, resveratrol has not shown promising beneficial effects. Vitamin C is beneficial in NAFLD patients. Vitamin E is not effectively regressing hepatic fibrosis. Hence, its combination with antifibrotic agents is used as an adjuvant to produce a synergistic antifibrotic effect. However, to date, none of these antioxidants have been used as a definite therapeutic agent in NAFLD patients. Further, these antioxidants should be studied in NAFLD patients with larger populations and multiple endpoints in the future.

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The effect of acetylsalicylic acid and pentoxifylline in guinea pigs with non‐alcoholic steatohepatitis

Cited by 9 publications

References 42 publications

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

Vitamin C Deficiency May Delay Diet-Induced NASH Regression in the Guinea Pig

A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases

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