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

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.

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Fatty acid oxidation and isoprostanes: Oxidative strain and oxidative stress

Prostaglandins Leukotrienes and Essential Fatty Acids ◽

10.1016/j.plefa.2010.02.031 ◽

2010 ◽

Vol 82 (4-6) ◽

pp. 219-225 ◽

Cited By ~ 36

Author(s):

Samar Basu

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

And Oxidative Stress

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Acute fatty liver of pregnancy: an update on mechanisms

Obstetric Medicine ◽

10.1258/om.2011.100071 ◽

2011 ◽

Vol 4 (3) ◽

pp. 99-103 ◽

Cited By ~ 7

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.

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

Health ◽

10.4236/health.2011.31009 ◽

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

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Plin5 deficiency exacerbates pressure overload-induced cardiac hypertrophy and heart failure by enhancing myocardial fatty acid oxidation and oxidative stress

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2019.07.006 ◽

2019 ◽

Vol 141 ◽

pp. 372-382 ◽

Cited By ~ 5

Author(s):

Chao Wang ◽

Yuan Yuan ◽

Jie Wu ◽

Yuanlin Zhao ◽

Xing Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Fatty Acid ◽

Cardiac Hypertrophy ◽

Fatty Acid Oxidation ◽

Pressure Overload ◽

Acid Oxidation ◽

Myocardial Fatty Acid ◽

And Oxidative Stress

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

Circulation Research ◽

10.1161/res.115.suppl_1.326 ◽

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.

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Activation of Peroxisome Proliferator-Activated Receptor (PPAR) Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

Diabetes ◽

10.2337/db07-1318 ◽

2007 ◽

Vol 57 (2) ◽

pp. 332-339 ◽

Cited By ~ 231

Author(s):

U. Riserus ◽

D. Sprecher ◽

T. Johnson ◽

E. Olson ◽

S. Hirschberg ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Metabolic Abnormalities ◽

Peroxisome Proliferator Activated Receptor

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A cafeteria diet triggers intestinal inflammation and oxidative stress in obese rats

British Journal Of Nutrition ◽

10.1017/s0007114516004608 ◽

2017 ◽

Vol 117 (2) ◽

pp. 218-229 ◽

Cited By ~ 18

Author(s):

K. Gil-Cardoso ◽

I. Ginés ◽

M. Pinent ◽

A. Ardévol ◽

X. Terra ◽

...

Keyword(s):

Oxidative Stress ◽

Intestinal Inflammation ◽

Cafeteria Diet ◽

Zucker Rats ◽

Standard Diet ◽

Metabolic Alterations ◽

Genetic Obesity ◽

Obesogenic Diet ◽

The Impact ◽

And Oxidative Stress

AbstractThe gastrointestinal alterations associated with the consumption of an obesogenic diet, such as inflammation, permeability impairment and oxidative stress, have been poorly explored in both diet-induced obesity (DIO) and genetic obesity. The aim of the present study was to examine the impact of an obesogenic diet on the gut health status of DIO rats in comparison with the Zucker (fa/fa) rat leptin receptor-deficient model of genetic obesity over time. For this purpose, female Wistar rats (n 48) were administered a standard or a cafeteria diet (CAF diet) for 12, 14·5 or 17 weeks and were compared with fa/fa Zucker rats fed a standard diet for 10 weeks. Morphometric variables, plasma biochemical parameters, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) levels in the ileum were assessed, as well as the expressions of proinflammatory genes (TNF-α and inducible nitric oxide synthase (iNOS)) and intestinal permeability genes (zonula occludens-1, claudin-1 and occludin). Both the nutritional model and the genetic obesity model showed increased body weight and metabolic alterations at the final time point. An increase in intestinal ROS production and MPO activity was observed in the gastrointestinal tracts of rats fed a CAF diet but not in the genetic obesity model. TNF-α was overexpressed in the ileum of both CAF diet and fa/fa groups, and ileal inflammation was associated with the degree of obesity and metabolic alterations. Interestingly, the 17-week CAF group and the fa/fa rats exhibited alterations in the expressions of permeability genes. Relevantly, in the hyperlipidic refined sugar diet model of obesity, the responses to chronic energy overload led to time-dependent increases in gut inflammation and oxidative stress.

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II. Cytochrome P-450 enzymes and oxidative stress

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.5.g1135 ◽

2001 ◽

Vol 281 (5) ◽

pp. G1135-G1139 ◽

Cited By ~ 215

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.

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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