Oxidative stress rather than triglyceride accumulation is a determinant of mitochondrial dysfunction in <i>in vitro</i> models of hepatic cellular steatosis

Lockman, K. A.; Baren, James P.; Pemberton, Christopher J.; Baghdadi, Hussam; Burgess, Karl; Plevris-Papaioannou, Nikolas; Lee, Patricia; Howie, Forbes; Beckett, G J; Pryde, Anne; Jaap, Alan J.; Hayes, Peter; Filippi, Céline; Plevris, John

doi:10.1111/j.1478-3231.2012.02775.x

Cited by 35 publications

(42 citation statements)

References 48 publications

(64 reference statements)

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“…Excessive energy substrates available to the hepatocytes can potentially cause cellular steatosis with the increasing generation of free fatty acids (FFA) and ROS, which, in turn, will lead to mitochondrial dysfunction inextricably linked with oxidative stress [19,20]. This is central to the development of dietary-induced NAFLD or TPN-associated liver disease under unbalanced nutrients perturbation and can potentially progress to steatohepatitis, fibrosis and cirrhosis in liver [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…This is central to the development of dietary-induced NAFLD or TPN-associated liver disease under unbalanced nutrients perturbation and can potentially progress to steatohepatitis, fibrosis and cirrhosis in liver [20,21]. …”

Section: Introductionmentioning

confidence: 99%

“…To address these questions, we used human C3A cells, a subclone of the hepatoma-derived HepG2 cell line treated with lactate, pyruvate and octanoate to induce TG accumulation and oxidative stress, allowing an exclusive and more efficient mitochondrial β-oxidation, which has been previously adopted as a model for hepatic cellular steatosis [20]. This study was further performed to investigate the effects of choline intervention on TG accumulation, Δψm, the methylation level of the PPARα DNA promoter and the expression of genes involved in hepatic lipid metabolism (FAS, PPARα, CPT-I) by using an in vitro hepatocellular steatosis model.…”

Section: Introductionmentioning

confidence: 99%

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The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Zhu

Tang

et al. 2014

Nutrients

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Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm) and glutathione peroxidase (GSH-Px) in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP)). Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM), reduced hepatocellular triglyceride (TG) accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS) production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM) partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I) and downregulating fatty acid synthase (FAS) gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

Zhu

Tang

et al. 2014

Nutrients

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“…In an in vitro study, energy-substrate treatment preserves mitochondrial function unaltered despite higher intracellular triglyceride accumulation. However, mitochondrial function impairment was apparent after 72 h due to ROS formation (Lockman et al, 2012). Therefore, the assessment of changes during short time intervals could be limiting, and prolonged culture times will be necessary to establish a mechanism of NASH development.…”

Section: Discussionmentioning

confidence: 96%

The interplay between hepatic stellate cells and hepatocytes in an in vitro model of NASH

Barbero-Becerra

Giraudi

Chávez-Tapia

et al. 2015

Toxicology in Vitro

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“…The mechanism in HCV infection includes increased lipogenesis, decreased degradation and impaired lipoprotein secretion [30]. Mitochondrial damage by iron-mediated ROS production may affect the lipid metabolism [31].…”

Section: Discussionmentioning

confidence: 99%

Effect of Iron-Mediated Oxidative Stress on Insulin Resistance Through the Forkhead Box-Containing Protein O Subfamily-1 (FOXO-1) Pathway in Chronic Hepatitis C

Kobayashi¹,

Iwasa²,

Miyachi³

et al. 2013

IJCM

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Aims: Chronic hepatitis C virus (HCV) infection is often associated with glucose metabolic disorders and iron overload. It has recently been shown that reactive oxygen species (ROS) increase gluconeogenesis in hepatocytes through the forkhead box-containing protein O subfamily-1 (FOXO1)-dependent pathway. The aim of this study is proving a causeand-effect relationship between iron-mediated ROS production and insulin resistance (IR) in chronic hepatitis C (CH-C) patients. Methods: The study included 42 patients with CH-C (22 males and 20 females, median age 53 years). Homeostasis model assessment of insulin resistance (HOMA-IR) value was assessed for each patient at entry. Gene expression levels in the biopsied liver tissues were determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, the effect of ROS on gluconeogenesis was assessed using HepG2 cells treated with a well-known ROS generator, diethylmaleate (DEM). Results: The serum ferritin levels were significantly correlated with the serum aspartate aminotransferase level, alanine aminotransferase level, HOMA-IR value, grade of fatty accumulation, total hepatic iron score, and 8-OH-deoxy-2'-guanosine (8-OHdG)-positive cell count. FOXO1 expression was correlated with 8-OHdG-positive cell count, phosphoenolpyruvate carboxykinase (PEPCK) expression, and HOMA-IR. In HepG2 cells, the gene transcription of FOXO1 and PEPCK was increased by DEM treatment, which was associated with an increase in non-phosphorylated FOXO1 protein in the nuclear fraction. Conclusions: Iron-mediated ROS production enhances gluconeogenesis through the FOXO1-mediated pathway and is an affecting factor to IR in patients with CH-C.

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Oxidative stress rather than triglyceride accumulation is a determinant of mitochondrial dysfunction in in vitro models of hepatic cellular steatosis

Abstract: Our data indicate that ROS formation, rather than cellular steatosis per se, impairs mitochondrial function. Thus, reduction in cellular steatosis may not always be the desired outcome without concomitant improvement in mitochondrial function and/or reducing of ROS formation.

Cited by 35 publications

References 48 publications

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

The interplay between hepatic stellate cells and hepatocytes in an in vitro model of NASH

Effect of Iron-Mediated Oxidative Stress on Insulin Resistance Through the Forkhead Box-Containing Protein O Subfamily-1 (FOXO-1) Pathway in Chronic Hepatitis C

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