The establishment of a novel non-alcoholic steatohepatitis model accompanied with obesity and insulin resistance in mice

Cong, Wei-na; Tao, Rongya; Tian, Jinying; Liu, Geng-Tao; Ye, Fei

doi:10.1016/j.lfs.2008.01.022

Cited by 87 publications

(66 citation statements)

References 39 publications

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“…25) PPARγ agonist could induce ABCAl transcription 26) ; Oxidative cholesterol can activate LXR for inducing ABCAl transcription; and the LXRα transcription is also affected by PPARγ. 27) Our results suggest that upregulation of PPARγ expressions in high-fat diet mice might be a compensatory and self-protection mechanism 12) ; And paeoniflorin decreased the levels of PPARγ mRNA. Paeoniflorin might restrain the PPARγ-LXRα-ABCA-1 pathway for lowering cholesterol.…”

Section: Discussionmentioning

confidence: 75%

Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice

Zhang

Yang

2015

Biological & Pharmaceutical Bulletin

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Paeoniflorin, a natural product and active ingredient of Paeonia lactiflora, has been demonstrated to have many pharmacological effects including antiinflammatory and antihyperglycemic activity. We investigated the effects of paeoniflorin on NAFLD in mice and its underlying mechanisms. We examined this hypothesis using a well-established animal model of NAFLD. The effects of paeoniflorin on inflammation and glucolipid metabolism disorder were evaluated. The corresponding signaling pathways were measured using real-time polymerase chain reaction (PCR). We demonstrated that the mice developed obesity, dyslipidemia, and fatty liver, which formed the NAFLD model. Paeoniflorin attenuated NAFLD and exhibited potential cardiovascular protective effects in vivo by lowering body weight, hyperlipidemia, and insulin resistance; blocking inflammation; and inhibiting lipid ectopic deposition. Further investigation revealed that the antagonistic effect on hyperlipidemia and lipid ectopic deposition was related to lowering the lipid synthesis pathway (de novo pathway, 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoAR)), promoting fatty acid oxidation [peroxisome proliferator-activated receptor-alpha (PPARα), carnitine palmitoyltransferase-1, etc.] and increasing cholesterol output (PPARγ-liver X receptor-α-ATP-binding cassette transporter-1); the inhibitory effects on inflammation and hyperglycemia were mediated by blocking inflammatory genes activation and reducing gluconeogenic genes expression (phosphoenolpyruvate carboxykinase and G6Pase). These results suggest that paeoniflorin prevents the development of NAFLD and reduces the risks of atherosclerosis through multiple intracellular signaling pathways. It may therefore be a potential therapeutic compound for NAFLD.

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Section: Discussionmentioning

confidence: 75%

Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice

Zhang

Yang

2015

Biological & Pharmaceutical Bulletin

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“…In this context, fenofibrate improved liver steatosis in animal models of obesity-related T2DM and hepatic insulin resistance [76,79] . Likewise, in a NASH animal model with obesity, dyslipidemia and insulin resistance fenofibrate improved insulin sensitivity and hepatic morphology, while decreasing ALT activity [77] . In this regard fenofibrate was more effective than rosiglitazone [77] .…”

Section: Clinical Evidencementioning

confidence: 90%

“…Likewise, in a NASH animal model with obesity, dyslipidemia and insulin resistance fenofibrate improved insulin sensitivity and hepatic morphology, while decreasing ALT activity [77] . In this regard fenofibrate was more effective than rosiglitazone [77] . Therefore, PPARα might be preferred over PPARγ activation for treating insulin resistance-associated NASH.…”

Section: Clinical Evidencementioning

confidence: 90%

“…Namely, it increased mRNA expression of FA β-oxidation enzymes in obese rats with T2DM [76] . These include FA transport protein, FA binding protein, carnitine palmitoyltransferase II, as well as medium-and longchain acyl-CoA dehydrogenase and acyl-CoA oxidase [76,77] . A high-fat diet-associated increase in the liver inflammatory gene expression may be ameliorated by fenofibrate [74] .…”

Section: Mechanistic Implicationsmentioning

confidence: 99%

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Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Kostapanos

Kei²,

Elisaf³

2013

WJH

131

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Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver-and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibraterelated PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

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“…The same authors stated that the groups fed with a high-fat diet and high-fructose water had higher TNFα levels, although no differences were observed in IL-1β mRNA levels (36). Cong et al quantifi ed PPARγ in a model of NASH using 23-week old C57BL/6 mice (ad libitum feeding with a high-fat diet, lower methinione and choline and higher fat content), and recorded significantly increased hepatic PPARγ mRNA expression (as well as suppressed hepatic PPARα mRNA expression) (37). No data on TOLLIP expression was available.…”

Section: Discussionmentioning

confidence: 99%

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

et al. 2017

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A, Pimentel-Nunes P. Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome. Rev Esp Enferm Dig 2017;109(7): 491-497. DOI: 10.17235/reed.2017491-497. DOI: 10.17235/reed. .4575/2016 Received: 26-08-201626-08- Accepted: 25-02-2017 Correspondence: Marta Borges-Canha. Department of Physiology and Cardiothoracic Surgery. Faculty of Medicine. University of Porto. Alameda Prof. Hernâni Monteiro. 4200-319 Porto, Portugal e-mail: marta.canha@gmail.com ABSTRACT Background:The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet.Aim: The characterization of liver histological and innate immunity changes in ZSF1 rats.Methods: Five groups of rats were included (n = 7 each group): healthy Wistar-Kyoto control rats (Ctrl), hypertensive ZSF1 lean (Ln), ZSF1 obese rats with a normal diet (Ob), ZSF1 obese rates with a high-fat diet (Ob-HFD), and ZSF1 obese rats with low-intensity exercise training (Ob-Ex). Results: Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05) than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison). Ob-HFD and Ob-Ex rats showed increased expression of PPARγ and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFα or IL-1 in any of the groups.Conclusion: The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or inflammation markers.

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The establishment of a novel non-alcoholic steatohepatitis model accompanied with obesity and insulin resistance in mice

Cited by 87 publications

References 39 publications

Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice

Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

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