II. Cytochrome P-450 enzymes and oxidative stress

2001 ◽  
Vol 281 (5) ◽  
pp. G1135-G1139 ◽  
Author(s):  
Graham Robertson ◽  
Isabelle Leclercq ◽  
Geoffrey C. Farrell
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Molecular Oxygen ◽  
Hepatic Steatosis ◽  
Nonalcoholic Steatohepatitis ◽  
Acid Oxidation ◽  
Cellular Injury ◽  
Second Hit ◽  
Cytochrome P 450 ◽  
And Oxidative Stress

Oxidative stress is present in the liver of humans with steatosis and nonalcoholic steatohepatitis (NASH) and is a plausible mediator of cellular injury, inflammatory recruitment, and fibrogenesis. CYPs 2E1 and 4A are the microsomal oxidases involved with fatty acid oxidation. Both enzymes can reduce molecular oxygen to produce prooxidant species, which, if not countered efficiently by antioxidants, create oxidative stress. In this theme article, we present the evidence that, in the context of hepatic steatosis, CYPs 2E1 and 4A could generate the “second hit” of cellular injury, particularly when antioxidant reserves are depleted, and propose ways in which this could contribute to the pathogenesis of NASH.

scholarly journals Acute fatty liver of pregnancy: an update on mechanisms

2011 ◽  
Vol 4 (3) ◽  
pp. 99-103 ◽  
Author(s):  
Sathish Kumar Natarajan ◽  
Kavitha R Thangaraj ◽  
Ashish Goel ◽  
C E Eapen ◽  
K A Balasubramanian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Fatty Liver ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Maternal Circulation ◽  
Subcellular Organelles ◽  
Microvesicular Steatosis ◽  
Acute Fatty Liver ◽  
And Oxidative Stress

Acute fatty liver of pregnancy (AFLP), characterized by hepatic microvesicular steatosis, is a sudden catastrophic illness occurring almost exclusively in the third trimester of pregnancy. Defective fatty acid oxidation in the fetus has been shown to be associated with this disease. Since the placenta has the same genetic makeup as the fetus and as AFLP patients generally recover following delivery, we hypothesized that the placenta might be involved in pathogenesis of this disease. In an animal model of hepatic microvesicular steatosis (using sodium valproate), we found that microvesicular steatosis results in mitochondrial structural alterations and oxidative stress in subcellular organelles of the liver. In placentas from patients with AFLP, we observed placental mitochondrial dysfunction and oxidative stress in subcellular organelles. In addition, defective placental fatty acid oxidation results in accumulation of toxic mediators such as arachidonic acid. Escape of these mediators into the maternal circulation might affect the maternal liver resulting in microvesicular steatosis.

scholarly journals Unbalanced biotransformation metabolism and oxidative stress status: implications for deficient fatty acid oxidation

Health ◽  
2011 ◽  
Vol 03 (01) ◽  
pp. 43-48
Author(s):  
Catharina M. Mels ◽  
Francois H. Van der Westhuizen ◽  
Pieter J. Pretorius ◽  
Elardus Erasmus
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Oxidative Stress Status ◽  
And Oxidative Stress

scholarly journals The Role of Mitochondria in Sex-Dependent Differences in Hepatic Steatosis and Oxidative Stress in Response to Cafeteria Diet-Induced Obesity in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1618
Author(s):  
Juliana Morais Mewes ◽  
Fabiana Rodrigues Silva Gasparin ◽  
Tiago Yoshida ◽  
Mariana Amâncio Daniel da Silva ◽  
Maria Raquel Marçal Natali ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Er Stress ◽  
Fatty Acid Oxidation ◽  
Liver Steatosis ◽  
Cafeteria Diet ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Mitochondrial Energy Metabolism ◽  
And Oxidative Stress

Female mice fed a cafeteria diet (FCaf) develop higher liver steatosis and oxidative stress than males (MCaf) as a consequence of unresolved ER stress. Here, we investigated whether mitochondria play a role in this sex difference. The isolated mitochondria from FCaf showed more signs of oxidative stress than those of MCaf, correlated with a reduced content of GSH, increased amount of reactive oxygen species (ROS), and lower activities of enzymes involved in ROS neutralisation. Mitochondria from FCaf and MCaf livers exhibited lower rates of succinate-driven state III respiration and reduced ATPase activity in intact coupled mitochondria compared to their controls fed a standard diet (FC and MC), with no differences between the sexes. Fatty acid oxidation in mitochondria and peroxisomes was higher in MCaf and FCaf compared to their respective controls. In the intact perfused liver, there was no difference between sex or diet regarding the fatty acid oxidation rate. These results indicated that cafeteria diet did not affect mitochondrial energy metabolism, even in FCaf livers, which have higher steatosis and cellular oxidative stress. Nevertheless, the increase in mitochondrial ROS generation associated with a decrease in the antioxidant defence capacity, probably contributes to inducing or reinforcing the ER stress in FCaf livers.

Abstract 326: Cd36 Deficiency Reduces Obesity-associated Inflammation And Oxidative Stress In Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Tahar Hajri ◽  
Mohamed Gharib ◽  
Thomas V Fungwe
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
P38 Mapk ◽  
Acid Oxidation ◽  
Cd36 Deficiency ◽  
Anti Oxidant ◽  
The Impact ◽  
And Oxidative Stress

OBJECTIVE: Obesity is often associated with diabetes and cardiovascular diseases (CVD). Mounting evidence shows that diabetes is associated with structural and functional changes in the heart. CD36 protein is highly expressed in heart and regulates lipid utilization in cardiacmyocytes. In this paper, we investigated the impact of CD36 expression on obesity-associated inflammation and oxidative stress in heart. METHODS: Studies were conducted in control lean (WT), obese leptin deficient (Lep Ob/Ob ) and leptin deficient-CD36 null (Lep Ob/Ob -CD36 -/- ) mice. To examine obesity-associated insulin resistance, glucose uptake and insulin signaling were examined in adult mouse hearts. Presence of macrophages in heart was examined with immunohistochemisty. Oxidative stress makers and activity of anti-oxidant enzymes were measured in hearts. To evaluate substrate utilization, glucose and fatty acid oxidation was tested in primary cultures of ventricular myocytes. Finally, the activity of pro-inflammatory kinases p38 mitogen-activated protein kinases (p38-MAPK), c-Jun NH2-terminal kinases (JNK) were examined in cardiacmyocytes challenged with palmitate. RESULTS: In Lep Ob/Ob , glucose uptake and oxidation in heart was lower than lean WT mice, while cardiac FA oxidation was strongly higher. Silencing CD36 in Lep Ob/Ob mouse markedly improved insulin sensitivity and glucose uptake in heart, but resulted in marked reduction of FA oxidation. Immunostaining of heart sections with macrophage specific antibody F4/80 showed that macrophage content was higher in myocardium of Lep Ob/Ob mice than Lep Ob/Ob -CD36 -/- mice. Moreover, oxidative stress markers, isoprostanes and reactive oxygen species, and expression of pro-inflammatory cytokines were higher in hearts of Lep Ob/Ob than Lep Ob/Ob -CD36-/- mice, although the activities of anti-oxidant enzymes were comparable. Chronic overload of Lep Ob/Ob cardiac myocyte with palmitate strongly induced the activity of JNK and p38-MAPK, but was less effective in Lep Ob/Ob -CD36 -/- cardiac myocytes. CONCLUSIONS: These results show that CD36 deficiency induced a significant reduction of obesity-associated oxidative stress and inflammation in heart in parallel to a drop in fatty acid oxidation.

Abstract 14844: Ampk is Required for Maintaining Atrial Metabolism and Oxidative Stress

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yina Ma ◽  
Xiaohong Wu ◽  
Xiaoyue Hu ◽  
Gary Cline ◽  
Fadi G Akar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Atrial Fibrillation ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Critical Role ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
And Oxidative Stress ◽  
Long Chain

Background: AMP-activated kinase (AMPK) has a critical role in cellular substrate and energy metabolism, regulating fatty acid oxidation, stimulating glucose transport and glycolysis. AMPK is crucial in the LV, preventing ischemic injury and heart failure. Atrial AMPK depletion induces atrial fibrillation in mice, but the role of AMPK in regulating atrial metabolism and oxidative stress is unknown. Methods: Atrial AMPK was selectively depleted in mice, utilizing sarcolipin-Cre mediated deletion of floxed α1 and α2 catalytic subunits (AMPKdKO). Floxed littermate mice were controls (CON). Microarray, immunoblotting, liquid chromatography-mass spectrometry (LC-MS), and electron microscope (EM) were used to access the gene, protein, metabolism, and mitochondria changes. Results: Pathway analysis of microarray data showed that fatty acid metabolism was downregulated in the AMPKdKO vs. CON atria (n=4 per group, p<0.0001). PGC1-α and downstream genes regulating fatty acid metabolism, including acyl-CoA thioesterase (ACOT), long-chain fatty acid-CoA ligase (ACSL), carnitine palmitoyltransferase 2 (CPT2), and fatty acid binding protein (FABP) were reduced in the AMPKdKO vs. CON atria (at 1 week of age). Atrial long-chain fatty acyl-CoA and acyl-carnitine levels were decreased (by LC-MS) in the AMPKdKO vs. CON atria (at 4 and 8 weeks of age) (n=3-4 per group, p<0.05). EM images showed evidence of swollen, broken and degraded mitochondrial in AMPKdKO atria (at 8 weeks age). Atrial expression of antioxidant enzymes, including SOD2 and PRDX3, was reduced (by immunoblotting) in AMPKdKO vs. CON atria (n=3-4, p<0.05). Conclusion: AMPK regulates critical mechanisms regulating atrial fatty acid metabolism and oxidative stress. Loss of atrial AMPK reduces the concentration of critical fatty acid intermediates for oxidative mitochondrial metabolism. These metabolic alterations may contribute to structural and electrical remodeling, and ensuing atrial fibrillation, that results from the loss of AMPK in the atria.

scholarly journals Gomisin N Alleviates Ethanol-Induced Liver Injury through Ameliorating Lipid Metabolism and Oxidative Stress

2018 ◽  
Vol 19 (9) ◽  
pp. 2601 ◽  
Author(s):  
Arulkumar Nagappan ◽  
Dae Jung ◽  
Ji-Hyun Kim ◽  
Hoyoung Lee ◽  
Myeong Jung
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Fatty Acid ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Antioxidant Genes ◽  
Gomisin N

Gomisin N (GN), a lignan derived from Schisandra chinensis, has been shown to possess antioxidant, anti-inflammatory, and anticancer properties. In the present study, we investigated the protective effect of GN against ethanol-induced liver injury using in vivo and in vitro experiments. Histopathological examination revealed that GN administration to chronic-binge ethanol exposure mice significantly reduced ethanol-induced hepatic steatosis through reducing lipogenesis gene expression and increasing fatty acid oxidation gene expression, and prevented liver injury by lowering the serum levels of aspartate transaminase and alanine transaminase. Further, it significantly inhibited cytochrome P450 2E1 (CYP2E1) gene expression and enzyme activity, and enhanced antioxidant genes and glutathione level in hepatic tissues, which led to decreased hepatic malondialdehyde levels. It also lowered inflammation gene expression. Finally, GN administration promoted hepatic sirtuin1 (SIRT1)-AMP-activated protein kinase (AMPK) signaling in ethanol-fed mice. Consistent with in vivo data, treatment with GN decreased lipogenesis gene expression and increased fatty acid oxidation gene expression in ethanol-treated HepG2 cells, thereby preventing ethanol-induced triglyceride accumulation. Furthermore, it inhibited reactive oxygen species generation by downregulating CYP2E1 and upregulating antioxidant gene expression, and suppressed inflammatory gene expression. Moreover, GN prevented ethanol-mediated reduction in SIRT1 and phosphorylated AMPK. These findings indicate that GN has therapeutic potential against alcoholic liver disease through inhibiting hepatic steatosis, oxidative stress and inflammation.

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