Recent Advances in Alcoholic Liver Disease II. Minireview: molecular mechanisms of alcoholic fatty liver

You, Min; Crabb, David W.

doi:10.1152/ajpgi.00056.2004

Cited by 199 publications

(165 citation statements)

References 25 publications

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…AMPK is known to downregulate fatty acid synthesis via reduced SREBP-1c expression 28 or ACC inactivation, 29 and reduced expression or activity of AMPK is implicated in alcoholic fatty liver. 30 However, neither AMPK ␣-subunit (AMPK␣) nor the activated form of AMPK, phosophorylated AMPK (p-AMPK), was changed in fatty livers of our obese mice (Fig. 5A).…”

Section: Resultsmentioning

confidence: 81%

Steatohepatitis Induced by Intragastric Overfeeding in Mice *

et al. 2005

View full text Add to dashboard Cite

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 ؎ 27 vs. 13 ؎ 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNF␣ and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPAR␥, LXR␣) was increased, whereas that of a lipolytic nuclear factor PPAR␣ was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a.

show abstract

Section: Resultsmentioning

confidence: 81%

Steatohepatitis Induced by Intragastric Overfeeding in Mice *

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The observation that mice deficient in TNF receptor 1 or endotoxin binding-signalling molecules develop less steatosis than wild-type animals (Arteel, 2003) suggests the possible involvement of oxidative mechanisms in the signals leading to Kupffer cell activation by endotoxins and/or in the metabolic effects of TNF-a (Dandona et al 2004). Nonetheless, it cannot be excluded that oxidative stress might also contribute to the effects of ethanol on the regulation of lipid metabolism by either the PPARa or the sterol regulatory element-binding protein 1 (You & Crabb, 2004). The induction of oxidative stress within liver mitochondria is associated with the collapse of mitochondrial membrane potential and the onset of mitochondrial permeability transition (MPT) (Hoek et al 2002).…”

Section: Oxidative Mechanisms and Mitochondrial Damage By Ethanolmentioning

confidence: 99%

Alcohol, oxidative stress and free radical damage

2006

View full text Add to dashboard Cite

The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease (ALD) is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of patients with alcoholism, as well as by experiments in alcohol-feed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. Ethanol-induced oxidative stress is the result of the combined impairment of antioxidant defences and the production of reactive oxygen species by the mitochondrial electron transport chain, the alcohol-inducible cytochrome P450 (CYP) 2E1 and activated phagocytes. Furthermore, hydroxyethyl free radicals (HER) are also generated during ethanol metabolism by CYP2E1. The mechanisms by which oxidative stress contributes to alcohol toxicity are still not completely understood. The available evidence indicates that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis and is implicated in the alcohol-induced sensitization of hepatocytes to the pro-apoptotic action of TNF-a. Moreover, oxidative mechanisms can contribute to liver fibrosis, by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells. Finally, the reactions of HER and lipid peroxidation products with hepatic proteins stimulate both humoral and cellular immune reactions and favour the breaking of self-tolerance during ALD. Thus, immune responses might represent the mechanism by which alcohol-induced oxidative stress contributes to the perpetuation of chronic hepatic inflammation. Together these observations provide a rationale for the possible clinical application of antioxidants in the therapy for ALD.

show abstract

“…Most studies on alcoholic hepatic steatosis have focused on the ability of ethanol to shift the redox state in the liver and to inhibit fatty acid oxidation [3,4] . Indeed, previous studies have shown the repression of some enzymes involved in fatty acid oxidation and induction of lipogenic enzymes in ethanol-fed animals [2,5] . The de novo synthesis of fatty acids in the liver was shown to increase with ethanol feeding in conjunction with the induction of adipogenic enzymes, including peroxisome proliferator-activated receptor alpha (PPAR alpha) and/or sterol regulatory element binding protein 1 (SREBP-1) [2,6] .…”

Section: Introductionmentioning

confidence: 96%

“…Alcohol is known to impair fat oxidation and to stimulate lipogenesis in the liver [2,3] . Thus, alcohol consumption can lead to the development of hepatic steatosis.…”

Section: Introductionmentioning

confidence: 99%

C/EBP beta and C/EBP delta expression is elevated in the early phase of ethanol-induced hepatosteatosis in mice

Chen

Yang²,

Chang

et al. 2009

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Alcohol, which is predominantly metabolized in the liver, is a major hepatic toxicant that readily induces hepatic steatosis. The expression of CCAAT enhancer binding protein (C/EBP), especially the C/EBP delta variety, is increased in the early phase of adipogenesis. However, the role of C/EBP delta in ethanol-induced hepatosteatosis is unclear. Methods: Male C57BL/6J mice were randomized to one of four groups: a control group, a group receiving orally administered ethanol (4 g ethanol/kg body weight) (EtOH), a high-fat-diet (HF) group and an EtOH+HF group. Mice were sacrifi ced after 5 or 10 weeks for various measurements. The in vitro effect of ethanol on the expression of C/EBP alpha, beta and delta was studied in HepG2 cells. Results: By week 5, ethanol treatment had signifi cantly increased liver C/EBP delta and beta protein expression (by 2.3-and 1.4-fold, respectively), which then returned to the control level by week 10. In contrast, the expression of C/EBP alpha was evident only at week 10. The in vitro study shows that C/EBP delta expression was elevated signifi cantly at 24 h but not at 48 or 72 h. C/EBP beta expression was highest at 48 h, whereas C/EBP alpha expression was highest at 72 h. We also found that a low concentration of ethanol plus oleic acid enhanced C/EBP delta expression in HepG2 cells. Conclusion: C/EBP delta expression appears to play an important role in the early phase of ethanol-induced hepatosteatosis in mice and in ethanol-treated HepG2 cells. In addition, EtOH+HF enhances the expression of C/EBP delta in HepG2 cells. Thus, C/EBP delta might be a therapeutic target in alcoholic hepatosteatosis.

show abstract

Recent Advances in Alcoholic Liver Disease II. Minireview: molecular mechanisms of alcoholic fatty liver

Cited by 199 publications

References 25 publications

Steatohepatitis Induced by Intragastric Overfeeding in Mice *

Steatohepatitis Induced by Intragastric Overfeeding in Mice *

Alcohol, oxidative stress and free radical damage

C/EBP beta and C/EBP delta expression is elevated in the early phase of ethanol-induced hepatosteatosis in mice

Contact Info

Product

Resources

About