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An ?-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.

ABSTRACT: Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ?-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ?-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study, we fed CCl4-treated mice a high ?-3 diet (using a mix of docosahexaenoic acid and eicosapentaenoic acid ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ?-3 and ?-6 dietary lipids. We showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ?-3-enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ?-3-enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ?-3-enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ?-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ?-3 diet groups.

SUBMITTER: Harris TR

PROVIDER: S-EPMC5102762 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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An ω-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.

Harris Todd R TR Kodani Sean S Yang Jun J Imai Denise M DM Hammock Bruce D BD

The Journal of nutritional biochemistry 20160914

Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4 ...[more]

PMID: 27732914

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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 ??smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, ??SMA, transforming growth factor (TGF)??1 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 ?-SMA, TGF-?1, collagen?1, VEGFR1, and VEGFR2. Levels of ??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.

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.

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An ?-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.

Publications

An ω-3-enriched diet alone does not attenuate CCl<sub>4</sub>-induced hepatic fibrosis.

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