Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis

Li, Hui; Toth, Erica; Cherrington, Nathan J.

doi:10.1093/toxsci/kfy106

Cited by 46 publications

(31 citation statements)

References 48 publications

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“…3b). Ethanol-treated Liver-Chips also exhibited significant changes in the expression of members of the alcohol dehydrogenase (ADH) gene family, including ADH1C 48 , ADH1B 49 and ADH1A, all involved in alcohol metabolism 49 .Most importantly, , we found that alcohol induced the expression of CYP2E1, critical for ethanol oxidation and the associated induction in oxidative stress (Fig. 3c).…”

Section: Ethanol-induced Steatosis In the Liver-chipmentioning

confidence: 73%

Modeling alcoholic liver disease in a human Liver-Chip

Nawroth

et al. 2020

Preprint

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Fatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis and for the development of sensitive noninvasive diagnostics and therapies. Alcohol-induced liver disease (ALD) represents an ideal case for modeling FDL as ethanol exposure is a comparatively simpler trigger for experimental induction of the pathology, as opposed to the complexity of modeling the diet- and life-style induced FLD. Further, despite their different root causes several common characteristics in disease progression and deterioration of liver function in the two disease entities, highlighting the potential of an ALD microphysiological model for broad application in translational research. Here, we leverage our recently reported human Liver-Chip for toxicity applications, to expand the capabilities of the platform for broad application in translational research. We report the first in vitro modeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. Importantly, we show that the ALD Liver-Chip supports the study of secondary insults, as patients with advanced ALD often show high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, owing to new developments in the design, the ALD Liver-Chip enables the measurement of structural changes of the bile canaliculi (BC) network as a novel in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury with direct translation to clinical research.

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Section: Ethanol-induced Steatosis In the Liver-chipmentioning

confidence: 73%

Modeling alcoholic liver disease in a human Liver-Chip

Nawroth

et al. 2020

Preprint

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“…The knockout of Pla2 has been proven to achieve a 56.5% decrease in fatty acid influx in hepatocytes . The administration of YZH liquid also increases the expression of alcohol dehydrogenase, the impairment of which has been noticed in the liver tissue of NASH patients . Overall, YZH liquid reduces hepatic lipid accumulation in HFHCD‐fed NASH rats by limiting lipogenesis and accelerating β‐oxidation.…”

Section: Discussionmentioning

confidence: 97%

Effects and therapeutic mechanism of Yinzhihuang on steatohepatitis in rats induced by a high‐fat, high‐cholesterol diet

Zeng

Liu

Xin

et al. 2020

J of Digest Diseases

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Objectives We aimed to investigate the therapeutic mechanism of Yinzhihuang (YZH) liquid, a traditional Chinese medicine mainly composed of extracts of four components, on nonalcoholic steatohepatitis (NASH) induced by a high‐fat, high‐cholesterol diet (HFHCD) in rats. Methods Altogether 30 Sprague‐Dawley rats were randomized into three groups: control, the model group (HFHCD + saline) and the treatment group (HFHCD + YZH). Liver histological features and serum biochemical parameters were assessed by the end of the 16th week. RNA sequencing and protein mass spectrometry detection were performed. The genes and proteins expressed differentially were subjected to KEGG pathway enrichment analysis and included in a network‐based regulatory model. Results The weight, liver and fat indices and serum alanine transaminase, aspartate transaminase and total cholesterol levels of the HFHCD + YZH group were all significantly lower than those of the HFHCD + saline group. Moreover, their hepatic steatosis, ballooning and lobular inflammation were relieved, and 64 hepatic genes and 73 hepatic proteins were found to be reversed in their expression patterns after YZH treatment (P < 0.05). The network‐based regulatory model showed that these deregulated genes and proteins were mainly involved in oxidative phosphorylation, Toll‐like receptor, nucleotide‐binding oligomerization domain‐like receptor, peroxisome proliferator‐activated receptor signaling, nuclear factor‐kappa B tumor necrosis factor signaling pathways and fatty acid metabolism. Conclusion YZH could alleviate NASH in HFHCD‐fed rats by inhibiting lipogenesis, accelerating lipid β‐oxidation, alleviating oxidative stress and relieving necroinflammation in the liver.

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“…Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease; alcohol dehydrogenase and aldehyde dehydrogenase collectively showed altered expression and function in the progression of nonalcoholic steatohepatitis (NASH) patients, which may also lead to significant alterations in the pharmacokinetics of substrate drugs. This information could be useful in making appropriate dosing adjustments for NAFLD patients taking drugs that are metabolized by these pathways [25].…”

Section: Discussionmentioning

confidence: 99%

Application of Bioactive Thermal Proteome Profiling to Decipher the Mechanism of Action of the Lipid Lowering 132-Hydroxy-pheophytin Isolated from a Marine Cyanobacteria

Amor

Freitas²,

Urbatzka³

et al. 2019

Marine Drugs

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The acceleration of the process of understanding the pharmacological application of new marine bioactive compounds requires identifying the compound protein targets leading the molecular mechanisms in a living cell. The thermal proteome profiling (TPP) methodology does not fulfill the requirements for its application to any bioactive compound lacking chemical and functional characterization. Here, we present a modified method that we called bTPP for bioactive thermal proteome profiling that guarantees target specificity from a soluble subproteome. We showed that the precipitation of the microsomal fraction before the thermal shift assay is crucial to accurately calculate the melting points of the protein targets. As a probe of concept, the protein targets of 132-hydroxy-pheophytin, a compound previously isolated from a marine cyanobacteria for its lipid reducing activity, were analyzed on the hepatic cell line HepG2. Our improved method identified 9 protein targets out of 2500 proteins, including 3 targets (isocitrate dehydrogenase, aldehyde dehydrogenase, phosphoserine aminotransferase) that could be related to obesity and diabetes, as they are involved in the regulation of insulin sensitivity and energy metabolism. This study demonstrated that the bTPP method can accelerate the field of biodiscovery, revealing protein targets involved in mechanisms of action (MOA) connected with future applications of bioactive compounds.

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Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis

Cited by 46 publications

References 48 publications

Modeling alcoholic liver disease in a human Liver-Chip

Modeling alcoholic liver disease in a human Liver-Chip

Effects and therapeutic mechanism of Yinzhihuang on steatohepatitis in rats induced by a high‐fat, high‐cholesterol diet

Application of Bioactive Thermal Proteome Profiling to Decipher the Mechanism of Action of the Lipid Lowering 132-Hydroxy-pheophytin Isolated from a Marine Cyanobacteria

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