Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease

Male Sprague-Dawley rats were chronically fed a high-unsaturated-fat diet for 130 days by using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g·kg−1·day−1. Relative to an ad libitum chow-fed group, the high-fat-fed controls had three- to fourfold greater expression of fatty acid transporter CD36 mRNA and developed mild steatosis but little other hepatic pathology. NAC treatment resulted in increased somatic growth relative to controls (4.0 ± 0.1 vs. 3.1 ± 0.1 g/day) and increased hepatic steatosis score (3.5 ± 0.6 vs. 2.7 ± 1.2), associated with suppression of the triglyceride hydrolyzing protein adiponutrin, but produced no elevation in serum alanine aminotransferase (ALT). Chronic EtOH treatment increased expression of fatty acid transport protein FATP-2 mRNA twofold, resulting in marked hepatic steatosis, oxidative stress, and a twofold elevation in serum ALT. However, no changes in tumor necrosis factor-α or transforming growth factor-β expression were observed. Fibrosis, as measured by Masson's trichrome and picrosirius red staining, and a twofold increase in expression of type I and type III collagen mRNA, was only observed after EtOH treatment. Long-term EtOH treatment increased hepatocyte proliferation but did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition. Although the effects of NAC on EtOH-induced fibrosis could not be fully evaluated, NAC had additive effects on hepatocyte proliferation and prevented EtOH-induced oxidative stress and necrosis, despite a failure to reverse hepatic steatosis.

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Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition

Physiological Genomics ◽

10.1152/physiolgenomics.00069.2012 ◽

2012 ◽

Vol 44 (22) ◽

pp. 1073-1089 ◽

Cited By ~ 19

Author(s):

M. J. J. Ronis ◽

J. N. Baumgardner ◽

J. C. Marecki ◽

L. Hennings ◽

X. Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Fatty Acid ◽

Enteral Nutrition ◽

Olive Oil ◽

Dietary Fat ◽

Hepatic Gene Expression ◽

Affymetrix Array ◽

Array Analysis ◽

Total Enteral Nutrition

To determine if dietary fat composition affects the progression of nonalcoholic fatty liver disease (NAFLD), we overfed male Sprague-Dawley rats low (5%) or high (70%) fat diets with different fat sources: olive oil (OO), corn oil (CO), or echium oil (EO), with total enteral nutrition (TEN) for 21 days. Overfeeding of the 5% CO or 5% EO diets resulted in less steatosis than 5% OO ( P < 0.05). Affymetrix array analysis revealed significant differences in hepatic gene expression signatures associated with greater fatty acid synthesis, ChREBP, and SREBP-1c signaling and increased fatty acid transport ( P < 0.05) in the 5% OO compared with 5% CO group. The OO groups had macrosteatosis, but no evidence of oxidative stress or necrosis. The 70% CO and 70% EO groups had a mixture of micro- and macrosteatosis or only microsteatosis, respectively; increased oxidative stress; and increased necrotic injury relative to their respective 5% groups ( P < 0.05). Oxidative stress and necrosis correlated with increasing peroxidizability of the accumulated triglycerides. Affymetrix array analysis comparing the 70% OO and 70% CO groups revealed increased antioxidant pathways and lower expression of genes linked to inflammation and fibrosis in the 70% OO group. A second study in which 70% OO diet was overfed for 50 days produced no evidence of progression of injury beyond simple steatosis. These data suggest that dietary fat type strongly influences the progression of NAFLD and that a Mediterranean diet high in olive oil may reduce the risk of NAFLD progressing to nonalcoholic steatohepatitis.

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PP014-SUN EFFECTS OF LONG-TERM HIGH-MONOUNSATURATED FATTY ACID ENTERAL FORMULA ON NUTRITIONAL STATUS, GLUCOSE AND FAT METABOLISM IN PATIENTS UNDER CONTINUOUS TOTAL ENTERAL NUTRITION

Clinical Nutrition Supplements ◽

10.1016/s1744-1161(12)70066-2 ◽

2012 ◽

Vol 7 (1) ◽

pp. 30

Author(s):

Y. Sakurai

Keyword(s):

Fatty Acid ◽

Enteral Nutrition ◽

Nutritional Status ◽

Fat Metabolism ◽

Monounsaturated Fatty Acid ◽

Enteral Formula ◽

Total Enteral Nutrition

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A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00296.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. G27-G38 ◽

Cited By ~ 86

Author(s):

January N. Baumgardner ◽

Kartik Shankar ◽

Leah Hennings ◽

Thomas M. Badger ◽

Martin J. J. Ronis

Keyword(s):

Oxidative Stress ◽

Enteral Nutrition ◽

Nonalcoholic Steatohepatitis ◽

Corn Oil ◽

Body Weight Gain ◽

Elevated Serum ◽

Fatty Acid Transport ◽

Liver Pathology ◽

Polyunsaturated Fat ◽

Total Enteral Nutrition

We have used total enteral nutrition (TEN) to moderately overfeed rats high-polyunsaturated fat diets to develop a model for nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal·kg−3/4·day−1 diet containing 5% (total calories) corn oil or a 220 kcal·kg−3/4·day−1 diet in which corn oil constituted 5, 10, 25, 35, 40, or 70% of total calories for 21 or 65 days. Rats fed the 5% corn oil, 220 kcal·kg−3/4·day−1 diet had greater body weight gain ( P ≤ 0.05), fat mass ( P ≤ 0.05), and serum leptin and glucose levels ( P ≤ 0.05), but no liver pathology. A dose-dependent increase in hepatic triglyceride deposition occurred with increase in percent corn oil in the 220 kcal·kg−3/4·day−1 groups ( P ≤ 0.05). Steatosis, macrophage infiltration, apoptosis, and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum alanine aminotransferase (ALT) levels ( P ≤ 0.05). An increase in oxidative stress (thiobarbituric acid-reactive substances) and TNF-α expression ( P ≤ 0.05) was observed in the 70% corn oil group, as well as an increase in hepatic CYP2E1 and CYP4A1 expression ( P ≤ 0.05). Significant positive correlations were observed between the level of dietary corn oil and the degree of pathology, ALTs, oxidative stress, and inflammation. Liver pathology was progressive with increased necrosis, accompanied by fibrosis, observed after 65 days of TEN. Increased expression of CD36 and l-fabp mRNA suggested development of steatosis was associated with increased fatty acid transport. These data suggest that intragastric infusion of a high-polyunsaturated fat diet at a caloric level of 17% excess total calories results in pathology similar to clinical NASH.

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Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification

Nature Communications ◽

10.1038/s41467-020-20839-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Inah Hwang ◽

Hiroki Uchida ◽

Ziwei Dai ◽

Fei Li ◽

Teresa Sanchez ◽

...

Keyword(s):

Oxidative Stress ◽

Environmental Changes ◽

Type I ◽

Neurogenic Differentiation ◽

Forkhead Box ◽

Nuclear Lamin ◽

Neural Stem Progenitor Cells ◽

Subsequent Activation ◽

Methyl Group Transfer

AbstractNeural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.

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Long-Term Ethanol Consumption Leadsto Lung Tissue Oxidative Stress and Injury

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.3.6.14417 ◽

2010 ◽

Vol 3 (6) ◽

pp. 414-420 ◽

Cited By ~ 10

Author(s):

Subir Kumar Das ◽

Sukhes Mukherjee

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Matrix Metalloproteinase ◽

Lung Tissue ◽

Ethanol Consumption ◽

Ethanol Exposure ◽

Lung Homogenate ◽

Ethanol Administration ◽

Metalloproteinase Activity

Background: Alcohol abuse is a systemic disorder. The deleterious health effects of alcohol consumption may result in irreversible organ damage. By contrast, there currently is little evidence for the toxicity of chronic alcohol use on lung tissue. Hence, in this study we investigated long-term effects of ethanol in the lung.Results: Though body weight of rats increased significantly with duration of exposure compared to its initial weight, there was no significant change in relative weight (g/100 g body weight) of lung due to ethanol exposure. The levels of thiobarbituric acid reactive substances (TBARS), nitrite, protein carbonyl, oxidized glutathione (GSS G), redox ratio (GSS G/ GSH ) and GST activity elevated; while reduced glutathione (GSH ) level and activities of glutathione reductase (GR), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD) and Na+K+ATPase reduced significantly with duration of ethanol exposure in the lung homogenate compared to the control group. Total matrix metalloproteinase activity elevated in the lung homogenate with time of ethanol consumption. Histopathologic examination also demonstrated that severity of lung injury enhanced with duration of ethanol exposure.Methods: 16–18 week-old male albino Wistar strain rats weighing 200–220 g were fed with ethanol (1.6 g/kg body weight/day) up to 36 weeks. At the end of the experimental period, blood samples were collected from reteroorbital plexus to determine blood alcohol concentration and the animals were sacrificed. Various oxidative stress-related biochemical parameters, total matrix metalloproteinase activity and histopathologic examinations of the lung tissues were performed.Conclusions: Results of this study indicate that long-term ethanol administration aggravates systemic and local oxidative stress, which may be associated with lung tissue injury.

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II. Cytochrome P-450 enzymes and oxidative stress

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.5.g1135 ◽

2001 ◽

Vol 281 (5) ◽

pp. G1135-G1139 ◽

Cited By ~ 215

Author(s):

Graham Robertson ◽

Isabelle Leclercq ◽

Geoffrey C. Farrell

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Molecular Oxygen ◽

Hepatic Steatosis ◽

Nonalcoholic Steatohepatitis ◽

Acid Oxidation ◽

Cellular Injury ◽

Second Hit ◽

Cytochrome P 450 ◽

And Oxidative Stress

Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the “second hit” of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.

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