Characterization of Hepatic Mitochondrial Injury Induced by Fatty Acid Oxidation Inhibitors

Vickers, Alison E. M.

doi:10.1177/0192623308329285

Cited by 61 publications

(48 citation statements)

References 54 publications

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“…Although direct perturbations to the mitochondrial membrane by inhibition of FAO - via accumulation of ceramide (14,33) or free fatty acids (44) - could be a proposed mechanism for the observed effects, our data suggest that EX does not lead to ceramide or long-chain fatty acyl-CoA accumulation in leukemia cells. Alternatively, it is conceivable that inhibition of mitochondrial FAO may result in increased generation of toxic dicarboxylic acids via microsomal ω-oxidation of excess fatty acids (45). Nevertheless, the synergism between orlistat (which does not promote ceramide or palmitate accumulation) and ABT-737 or Nutlin 3a motivates us to contemplate the possibility that fatty acid entry and/or FAO in mitochondria may ipso facto be involved in the regulation of the Bcl-2 apoptotic rheostat in leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Samudio¹,

Harmancey²,

Fiegl³

et al. 2010

J. Clin. Invest.

602

559

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The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling -the continuing reduction of oxygen without ATP synthesis -has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells -cultured alone or on bone marrow stromal cells -to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies. IntroductionMore than half a century ago, Otto Warburg proposed that the origin of cancer cells was closely linked to a permanent respiratory defect that circumvents the Pasteur effect, i.e., the inhibition of anaerobic fermentation by oxygen (1). However, we have recently demonstrated that in leukemia cells, mitochondrial uncoupling - the continuing reduction of oxygen without the synthesis of ATP - could mimic the Warburg effect in the absence of permanent, transmissible alterations to the oxidative capacity of cells (2). This metabolic pattern was observed when leukemia cells were cultured on feeder layers of bone marrow-derived mesenchymal stromal cells (MSCs). MSCs have previously been reported to support both normal and malignant hematopoiesis (reviewed in refs. 3-5) and have become an important component in the in vitro modeling of the bone marrow microenvironment. Leukemia cells cultured on MSC feeder layers demonstrated increased lactate generation, and, most curiously, decreased mitochondrial membrane potential in the presence of a transient (6-8 hour) increase in oxygen consumption. Additionally, this uncoupled phenotype appeared to be associated with the antiapoptotic effect of MSC feeder layers, and we hypothesized a shift away from the complete oxidation of glucose. This concept has already been alluded to by Lynen (6), and by Ronzoni and Ehrenfest in experiments using the prototypical protonophore 2,4-dinitrophenol, and suggests a metabolic shift to fatty acid oxidation (FAO) rather than pyruvate oxidation (2, 7). Although i...

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Section: Discussionmentioning

confidence: 99%

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Samudio¹,

Harmancey²,

Fiegl³

et al. 2010

J. Clin. Invest.

602

559

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“…8) When NAFLD occurs, excess FFAs in the liver cells lead to the development of lipid peroxidation and the generation of a large number of ROS, which are the major indicators of oxidative stress. 43) Consequently, ROS prompt the generation of TNF-α, which inhibits mitochondria respiration and induces and aggravates insulin resistance. 44,45) Superoxide dismutase (SOD) is an important antioxidant enzyme and the primary means of free radicals scavenging in organisms.…”

Section: Discussionmentioning

confidence: 99%

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

Gao

Zeng

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been demonstrated to reduce hepatic steatosis. However, the mechanism of the lipid-lowering effect of liraglutide in the liver remains unclear. The aim of the present study was to investigate the beneficial effect of liraglutide on diet-induced non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism in rats. NAFLD was induced in Sprague-Dawley rats by feeding a high fat and high cholesterol (HFHC) diet. Liraglutide (0.6 mg/kg body weight/d) was injected intraperitoneally to the rats subjected to HFHC diet four weeks before sacrificing the animals. Body and liver weight, fasting blood glucose (FBG), fasting insulin, serum aminotransferase (ALT) and lipid accumulation in the liver were determined. Markers of oxidative stress, such as malondialdehyde (MDA), free fatty acid (FFAs), superoxide dismutase (SOD), and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) were detected by colorimetric detection or enzyme-linked immunosorbent assay (ELISA). Serum and hepatic adiponectin were measured by ELISA. The expression of c-Jun N-terminal kinase-1 (JNK-1) and phosphorylated JNK-1 were examined by Western blotting. Liraglutide improved insulin resistance, decreased hepatic steatosis and reversed liver dysfunction. The hepatic levels of MDA, FFAs, and TNF-α were significantly decreased versus controls. Meanwhile, administration of liraglutide significantly increased SOD and adiponectin levels in the liver and inhibited the expression of JNK-1 and phosphorylated JNK-1 versus control rats. Liraglutide exerted anti-oxidative and anti-inflammatory effects in the liver and consequently reversed hepatic steatosis and insulin resistance. Such effects might be mediated by the elevation of adiponectin levels and the inactivation of JNK-1.

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“…Cytoplasmic vacuolation was also observed in some hepatocytes, which strongly suggest the presence of ultrastructural changes include deposition of fat droplets (Watanabe and Yanagita, 1983), excess accumulation of glycogen (Nayak et al, 1996), mitochondrial changes (Vickers, 2009), and multiple vacuoles with poor cytoplasmic architecture (Adewole and Ojewole, 2007). Our findings concerning increasing values of AST, ALT and LDH, as well as appearance of necrosis caused by acetone treatment are in agreement with those of other authors who showed that, the appearance of necrosis with vacuolation seemed to be associated with increased levels of hepatic biomarkers such as ALT, AST and LDH (Shimada et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Acetone Induced Liver and Kidney Injury by Ginger and Turmeric Root Powder in Chickens

El‐Rahman

Elwan

El-Shafei

et al. 2018

AJAS

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Ginger and turmeric are commonly used in food as spices with wellreported antioxidant activity. However, hepatoprotective and nephroprotective effects of ginger and turmeric have not been adequately studied. Therefore, the current study used chicken model with acetone induced liver and kidney injuries to evaluate the hepatoprotective and nephroprotective activities of ginger and turmeric because metabolic functions of chicken and human liver is similar. Eighty cocks were randomized into 5 experimental groups of chicks. The first one served as control. While the second group was received 350mg acetone/kg body weight (given in drinking water) per day for 30 days. The third, fourth and fifth groups were received ginger, turmeric and mix of ginger and turmeric by 1% in food respectively after treatment with acetone. Hematological parameters, liver and renal function tests, hepatic oxidative stress enzymes, as well as, histopathological examination scores were determined. Results indicated that, administration of acetone induces alteration in various hematological parameters, hepatic enzymes and hepatic oxidative stress enzymes in chickens. Dietary supplementation of ginger (GEN) and turmeric (TUR) caused a significant amelioration in some hematological parameters in acetone treated chickens. GEN and TUR treatments could reduce damage induced by acetone in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), glucose, total protein and their fractions levels. Furthermore, acetone promoted a significant increase in urea, uric acid and creatinine levels, while treatment with GEN or TUR or GEN+TUR at the same time of treatment with acetone maintained urea and uric acid concentrations at a level similar to the control group. Interestingly, GEN, TUR and GEN+ TUR treatments significantly ameliorated effects of acetone on chickens by improving the levels of the main antioxidant enzymes (superoxide dismutase SOD, glutathione-S-transferase GST) and malondialdehyde (MDA) a reliable marker of lipid peroxidation in the cells. Histologically, acetone appeared to be hepatotoxic in chick's. Hepatocytes were sensitive to the treatment with acetone and contained large number of congested blood vesicles, cytoplasmic vacuoles, pyknotic nuclei, and lymphocytic infiltration in treated animals. Turmeric and ginger treatments improved the vast majority of hepatic changes. Our findings broadly confirmed that, the supplementation of ginger and turmeric significantly alleviated liver and kidney functions, hema-

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Characterization of Hepatic Mitochondrial Injury Induced by Fatty Acid Oxidation Inhibitors

Cited by 61 publications

References 54 publications

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease

Attenuation of Acetone Induced Liver and Kidney Injury by Ginger and Turmeric Root Powder in Chickens

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