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Fast food diet with CCl4 micro-dose induced hepatic-fibrosis--a novel animal model.

ABSTRACT: BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use. Several animal models capture aspects of NAFLD but are limited either in their representation of the disease stages or use for development of therapeutics due to the extended periods of time required to develop full histological features. METHODS: Here, we report the development of a novel rat model for NAFLD that addresses some of these limitations. We used a fast food diet (FFD) and a CCl4 micro dose (0.5 ml/kg B.wt) for 8 weeks in Wistar rats. Serological analyses, gene expression profiling and liver histology studies were conducted to investigate the development of steatosis, steatohepatitis and fibrosis in the FFD-CCl4 model when compared to the individual effects of a FFD or a micro dose of CCl4 in rats. RESULTS: The serum biochemical profile of the FFD-CCl4 model showed an increase in liver injury and fibrosis. This was also accompanied by a significant increase in liver triglycerides (TG), inflammation and oxidative stress. Importantly, we observed extensive fibrosis confirmed by: i) increased gene expression of fibrosis markers and, ii) moderate to severe collagen deposition seen as perisinusoidal and bridging fibrosis using H&E, Trichome and Sirius Red staining. CONCLUSIONS: In summary, we find that the FFD-CCl4 rat model developed NAFLD histological features including, steatosis, inflammation and fibrosis in 8 weeks showing promise as a model that can be used to develop NAFLD therapeutics and liver anti-fibrotics.

SUBMITTER: Chheda TK

PROVIDER: S-EPMC4036109 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Fast food diet with CCl4 micro-dose induced hepatic-fibrosis--a novel animal model.

Chheda Tarak K TK Shivakumar Pratibha P Sadasivan Satish Kumar SK Chanderasekharan Harish H Moolemath Yogananda Y Oommen Anup M AM Madanahalli Jagannath R JR Marikunte Venkataranganna V VV

BMC gastroenterology 20140510

<h4>Background</h4>Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use. Several animal models capture aspects of NAFLD but are limited either in their representation of the disease stages or use for development of therapeutics due to the extended periods of time required to develop full histological features.<h4>Methods< ...[more]

PMID: 24884574

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Project description:Hepatic fibrosis is resulted from sustained wound-healing responses to various harmful stimuli, including viral infection, drug toxicity, alcohol, and autoimmune hepatopathy, and it has recently attracted the attention of an increasing number of researchers and clinical workers. The aims of this study were to examine the anti-fibrotic effects of extracts of Periplaneta americana (EPA) on CCl4-induced hepatic fibrosis in rats, to preliminary determine the anti-fibrotic efficacy of EPA, and to identify a potential and effective therapeutic agent to attenuate hepatic fibrosis. In this study, we routinely detected liver functional indices, such as alanine aminotransferase (ALT), aspartate transaminase (AST), and albumin (Alb). We also measured hepatic fibrosis-related serum markers, including hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), and type IV collagen (IV-C) via radioimmunoassay. Moreover, we examined histological activity and fibrosis stage via light microscopy after hematoxylin and eosin and Masson staining. Furthermore, we detected the expressions of nuclear factor-kappa B (NF-κB), alpha-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and tissue inhibitor of metalloprotease-1 (TIMP-1) in rat liver tissues by immunohistochemical staining. We found that EPA, whose main components are viscous sugar amino acids, can reduce the levels hepatic fibrosis-related factors, including HA, LN, PC III, and IV-C, improve liver function, attenuate, or reverse pathological damage associated with hepatic fibrosis, and thus inhibit the progression of hepatic fibrosis. The mechanism of EPA action may be related to the inhibition of TGF-β1, NF-κB, and α-SMA expressions and the reduction of TIMP-1 levels in the liver to reduce the accumulation of extracellular matrix (ECM) components, thereby blocking the relevant signaling pathways and preventing inflammatory responses to attenuate or reverse hepatic fibrosis. EPA may thus be used as a potentially effective therapeutic agent for the treatment of hepatic fibrosis.

Project description:Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)‑induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α‑smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α‑SMA, transforming growth factor (TGF)‑β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT‑qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen‑1, VEGFR1, and VEGFR2. Levels of α‑SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.

Dataset Information

Fast food diet with CCl4 micro-dose induced hepatic-fibrosis--a novel animal model.

Publications

Fast food diet with CCl4 micro-dose induced hepatic-fibrosis--a novel animal model.

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