Alcoholic and non-alcoholic steatohepatitis

Neuman, Manuela G.; French, Samuel W.; French, Barbara A.; Seitz, Helmut K.; Cohen, Lawrence B.; Mueller, Sebastian; Osna, Natalia A.; Kharbanda, Kusum K.; Seth, Devanshi; Bautista, Abraham P.; Thompson, Kyle J.; McKillop, Iain H.; Kirpich, Irina; McClain, Craig J.; Bataller, Ramón; Nanau, Radu M.; Voiculescu, M; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomes, Paul; Ganesan, Murali; Malnick, Stephen

doi:10.1016/j.yexmp.2014.09.005

Cited by 59 publications

(70 citation statements)

References 230 publications

(240 reference statements)

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“…Alcohol-induced liver disease (ALD) is a leading cause of nonaccident-related deaths in the United States due in large part to liver injury, notably alcoholic liver disease and liver cirrhosis [52]. Mice lacking PPARα are higly susceptible to ALD, thus making them an excellent model to study the mechanisms of this disease [53].…”

Section: Alcohol-induced Liver Diseasementioning

confidence: 99%

Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity

Gonzalez

Fang

2015

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically-modified mouse models and metabolomics. Areas covered Gene knockout mice can be used to determine the enzymes responsible for the metabolism of xenobiotics in vivo and to examine the mechanisms of xenobiotic-induced toxicity. Humanized mouse models are especially important since there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing cytochromes P450 (CYPs) and nuclear receptors including the pregnane X receptor (PXR), the major regulator of xenobiotic metabolism and transport were produced. With genetically-modified mouse models, metabolomics can determine the molecular map of many xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of xenobiotic toxicity and to find early biomarkers for toxicity. Expert opinion Metabolomics and genetically-modified mouse models can be used for the study of xenobiotic metabolism and toxicity by: 1) Comparison of the metabolomics profiles between wild-type and genetically-modified mice, and searching for genotype-dependent endogenous metabolites; 2) Searching for and elucidating metabolites derived from xenobiotics; 3) Discovery of specific alteration of endogenous compounds induced by xenobiotics-induced toxicity.

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Section: Alcohol-induced Liver Diseasementioning

confidence: 99%

Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity

Gonzalez

Fang

2015

Expert Opinion on Drug Metabolism & Toxicology

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“…Previously, progression of NAFLD has been associated with genetic predisposition, insulin resistance, hepatic iron storage, as well as inflammatory events or mediators including adipokines, endotoxins and oxidative stress leading to apoptosis and necrosis. [3,4] Although the mechanisms precipitating release of inflammatory mediators or induction of cell death pathways are not fully understood, intestinal and hepatic handling of cytotoxic bile acids may be involved.…”

Section: Introductionmentioning

confidence: 99%

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

et al. 2015

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Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. Methods Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial timepoints following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. Results Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH: 2595–3549 μM and healthy: 1171–1458 μM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH: 4444–5898 μM and healthy: 2634–2829 μM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. Conclusions Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

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“…For instance, people who drink more than 60 g/day are more likely to develop fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure (Lucey, Mathurin, & Morgan, 2009;. In addition, simultaneous exposure to alcohol and one or two of these risk factors significantly increase the severity of liver disease with elevated morbidity and mortality (Neuman et al, 2014). In this review, we briefly describe the mechanisms of various types of liver disease caused by alcohol (ethanol), HFD, or other potentially hepatotoxic substances and the enzymes involved in the alcohol metabolism in promoting liver disease.…”

Section: Introductionmentioning

confidence: 99%