NASH: a mitochondrial disease

Pessayre, Dominique; Fromenty, Bernard

doi:10.1016/j.jhep.2005.03.004

Cited by 394 publications

(376 citation statements)

References 127 publications

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“…High OS has been described previously to be associated with obesity [28,29]. Also, there is accumulating evidence that mitochondrial dysfunction (more particularly respiratory chain defects) plays an important role in the pathophysiology of advanced forms of NAFLD, whatever its initial cause [29,30]. Mitochondrial beta-oxidation of fatty acids can be increased, such as in insulin resistance-associated NAFLD, or decreased, as in drug-induced NAFLD [31,32].…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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

et al. 2008

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“…Although less well studied, there is also evidence that defective mitochondrial function in liver is associated with insulin resistance in rodent models of insulin resistance [47]. In addition, mitochondrial abnormalities such as depletion of mitochondrial DNA, decreased activity of respiratory chain complexes, and impaired mitochondrial β-oxidation and mitochondrial DNA complexes have been observed in patients with non-alcoholic fatty liver disease [48,49]. IL-6 treatment has previously been shown to decrease oxidative injury after 87% hepatectomy in mice [50].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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“…12 Several studies have documented the possible role of decreased liver fatty acid oxidation in the development and progression of NAFLD and hypothesized that impaired mitochondrial function may be involved. [29][30][31] In summary, these studies showed that decreased hepatic mitochondrial fatty acid oxidation was associated with increased hepatic triacylglycerol accumulation. Supporting these data, HFD-induced obesity in mice was associated with increased hepatic peroxisome proliferator-activated receptor-γ, carnitine palmitoyltransferase-1, and acetyl-CoA carboxylase, and these changes were associated with decreased serum triacylglycerol.…”

Section: -13mentioning

confidence: 93%

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

et al. 2013

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Abstract-Angiotensin (Ang)-(1-7) has been described as an important tool on treating and preventing metabolic disorders. In this study, we aimed to evaluate the effect of an oral formulation of Ang-(1-7) included in hydroxypropylβ-cyclodextrin (HPβCD/Ang- [1][2][3][4][5][6][7]) on hepatic function, steatosis, and on liver inflammatory markers expression in mice treated with a high-fat diet. Male FVB/N mice were divided into 4 groups and fed for 60 days, with each group receiving 1 of the following diets: standard diet+HPβCD, standard diet+Ang-(1-7)/HPβCD, high-fat diet+HPβCD, or highfat diet+Ang-[1-7]/HPβCD. Body weight, food intake, and blood parameters, such as total cholesterol, triglyceride, alaninetransaminases, and aspartate transaminases, were evaluated. Immunohistochemical analyses were performed for inflammatory markers tumor necrosis factor-α and interleukin-6. Expression of angiotensin converting enzyme, angiotensin-converting enzyme-2, interleukin-1β, tumor necrosis factor-α, interleukin-6, transforming growth factor-β, acetyl-CoA carboxylase, carbohydrate-responsive element-binding protein, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins-1c was evaluated by quantitative real-time polymerase chain reaction. The major findings of our study included reduced liver fat mass and weight, decreased plasma total cholesterol, triglyceride, and alaninetransaminase enzyme levels in the oral Ang-(1-7)-treated groups compared with the control groups. These results were accompanied by a significant reduction in tumor necrosis factor-α and interleukin-6 mRNA expression in the liver. Analyses of liver adipogenesis-related genes by quantitative real-time polymerase chain reaction showed that acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins1c mRNA expression were significantly suppressed. In conclusion, we observed that treatment with Ang-(1-7) improved metabolism and decreased proinflammatory profile and fat deposition in liver of mice. The renin-angiotensin system (RAS) is now recognized to play an important role in the development of cardiovascular and metabolic disorders. [10][11][12][13] The RAS consists primarily of an enzymatic cascade in which angiotensinogen is converted to angiotensin (Ang) I and subsequently to Ang II by the actions of renin and Ang-converting enzyme (ACE), respectively. 14 Ang-(1-7) is formed mainly from Ang II by ACE-2 and indirectly from Ang I.14 The ACE-2/Ang-(1-7)/Mas axis has been suggested as an important counter-regulatory arm in the RAS with effects opposing those of ACE/Ang II/Ang II receptor, type 1. 13Recent studies showed an important participation of RAS in the nonalcoholic fatty liver disease (NAFLD) development and progression. The Ang II has been implicated as a major player in the altered hepatic lipid metabolism observed in NAFLD. Genetic disruption of several RAS components in rodent models results in a protection from high-fat diet (HFD)-induced obesity. [15...

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NASH: a mitochondrial disease

Cited by 394 publications

References 127 publications

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

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

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

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