Mitochondrial Adaptations to Obesity-Related Oxidant Stress

Yang, Shiqi; Zhu, Hong; Li, Yunbo; Lin, Huizhi; Gabrielson, Kathleen; Trush, Michael A.; Diehl, Anna Mae

doi:10.1006/abbi.2000.1829

Cited by 338 publications

(247 citation statements)

References 60 publications

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“…More importantly, the molecular mechanisms responsible for oxidant production in obesity induced fatty liver are not known, especially because mitochondrial un-coupling has been shown in experimental models of NAFLD [51]. Studies using liver mitochondria from ob/ob mice have however demonstrated increased O 2 • − compared to mitochondria from lean mice [60,61]. Possible mechanisms for enhanced mitochondrial ROS production include molecular defects within Complexes I and III, as well as increases in RLS, and TNFα mediated ceramide [22,59,62,63].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

“…Conflicting effects of obesity and NAFLD on mitochondrial GSH levels have also been reported. For example, decreased [53] and increased [61] levels of mitochondrial GSH have been reported in liver of ob/ob mice. In addition, two glutathione-replenishing agents, S-adenosylmethionine and 2(RS)-npropylthiazolidine-4(R)-carboxylic acid (i.e.…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

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Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

374

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

374

302

View full text Add to dashboard Cite

show abstract

“…Biochemical and histological improvement after treatment with antioxidants in NAFLD is an indirect evidence of OSinduced pathogenesis [14]. Increased levels of ROS and products of lipid peroxidation have also been demonstrated in this condition [15,16]. But most of the studies included small number of patients and the results in many of these studies are conflicting and show only weak associations.…”

Section: Introductionmentioning

confidence: 99%

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

et al. 2008

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Purpose Altered redox status has been implicated in pathogenesis of alcoholic liver disease (ALD) as well as in nonalcoholic fatty liver disease (NAFLD). This study was planned to find the relative role of redox status in these two diseases. Methods A total of 44 patients with ALD and 32 patients with NAFLD and 25 apparently healthy controls were included in the study. Redox status was estimated by measuring oxidative stress (superoxide dismutase (SOD) and lipid peroxidation products as thiobarbituric acid reactive substances (TBARS)) and antioxidant status (ferric reducing ability of plasma (FRAP) and vitamin C). Results TBARS level was raised significantly in both ALD (3.5 (2.3-9.4) vs. 1.8 (0.5-4.1) nmol/ml; P = 0.0001) and NAFLD (5.1 (1-10.2) vs. 1.82 (0.51-4.1) nmol/ml; P = 0.0001) as compared with controls, but was not different between ALD and NAFLD. SOD was significantly higher in ALD as compared to NAFLD (2.4 (1.3-7.8) vs. 0.68 (0.05-19.1) U/ml; P = 0.0001) and controls (1.12 (0.01-3.5) U/ml; P = 0.001). FRAP was lower in ALD as compared with 3) lmol of Fe +2 liberated; P = 0.001) but similar to that of controls (340.9 (141.5-697.5) lmol of Fe +2 liberated). Conclusions ALD patients have a higher degree of redox imbalance as compared with NAFLD patients

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“…In nonparenchymal liver cells, induction of UCP2 is associated with a decrease in H 2 O 2 production [131]. The ob/ob mouse has increased susceptibility to inflammatory hepatic lesions associated with a 200 % increase in ROS generation by hepatocyte mitochondria [132]. Models of fatty liver, including ob/ob mice, exhibit an increase in UCP2 mRNA, which is hypothesized to be an adaptive response to ROS [132,133].…”

Section: Regulation Of Reactive Oxygen Species Productionmentioning

confidence: 99%

“…The ob/ob mouse has increased susceptibility to inflammatory hepatic lesions associated with a 200 % increase in ROS generation by hepatocyte mitochondria [132]. Models of fatty liver, including ob/ob mice, exhibit an increase in UCP2 mRNA, which is hypothesized to be an adaptive response to ROS [132,133]. Of interest, PPAR-g mRNA is increased in ob/ob mouse hepatocytes and treatment with a PPAR-g ligand induces a further increase in UCP2 expression [134].…”

Section: Regulation Of Reactive Oxygen Species Productionmentioning

confidence: 99%

Uncoupling protein-2: evidence for its function as a metabolic regulator

2002

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Uncoupling protein-2 (UCP2) was discovered in 1997 but a definitive understanding of its functions has so far eluded investigators. Potential roles include regulating fat metabolism directly and indirectly via effects on insulin secretion. Also, UCP2 could also negatively modulate the production of reactive oxygen species (ROS). Although evidence in support of these functions is correlational, research on UCP2 mechanisms of action has recently been published. Studies of polymorphisms in the uncoupling protein-2 gene have not been included in detail here but are reviewed elsewhere [1,2]. For an in depth discussion of the uncoupling protein family of proteins, readers are referred to recent reviews [1, 3]. Chemical properties of uncoupling proteinsMitochondrial metabolism generates more than 90 % of the ATP required by organisms for routine cellular processes. The efficiency of ATP formation could be altered by demand, by drugs or by pathological processes. Uncoupling agents dissociate fuel oxidation in the electron transport chain of mitochondria from phosphorylation of substrate, namely ADP. Normally, glucose-derived NADH and FADH 2 stimulate Diabetologia (2002) AbstractUncoupling protein-2, discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as carriers. The function(s) of uncoupling protein-2 have not yet been definitively described. However, mounting evidence suggests that uncoupling protein-2 could act in multiple tissues as a regulator of lipid metabolism. A role as a modulator of reactive oxygen species as a defence against infection is also postulated. In this review, a brief overview of the general and specific properties of uncoupling protein-2 is given and evidence for metabolic and immune regulatory functions is summarized.Uncoupling protein-2 could have particular importance in the regulation of lipid metabolism in adipose tissue and skeletal muscle. In addition, its ability to inhibit insulin secretion could also promote fat utilization over storage. Inhibition by uncoupling protein-2 of reactive oxygen species formation in macrophages and other tissues could have implications for regulation of immune function. The possibility of functions of uncoupling protein-2 in other tissues such as the brain are beginning to emerge. [Diabetologia (2002) 45: 174±187]

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Mitochondrial Adaptations to Obesity-Related Oxidant Stress

Cited by 338 publications

References 60 publications

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

Uncoupling protein-2: evidence for its function as a metabolic regulator

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