scholarly journals Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2

2021 ◽  
Vol 8 ◽  
Author(s):  
Andrea Eynaudi ◽  
Francisco Díaz-Castro ◽  
Juan Carlos Bórquez ◽  
Roberto Bravo-Sagua ◽  
Valentina Parra ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Damage ◽  
Atp Synthesis ◽  
Acid Oxidation ◽  
Mitochondrial Potential ◽  
Differential Effects ◽  
Highly Active ◽  
Triglyceride Accumulation ◽  
Joint Dynamics ◽  
Palmitic Acids

Fatty acid overload, either of the saturated palmitic acid (PA) or the unsaturated oleic acid (OA), causes triglyceride accumulation into specialized organelles termed lipid droplets (LD). However, only PA overload leads to liver damage mediated by mitochondrial dysfunction. Whether these divergent outcomes stem from differential effects of PA and OA on LD and mitochondria joint dynamics remains to be uncovered. Here, we contrast how both fatty acids impact the morphology and interaction between both organelles and mitochondrial bioenergetics in HepG2 cells. Using confocal microscopy, we showed that short-term (2–24 h) OA overload promotes more and bigger LD accumulation than PA. Oxygen polarography indicated that both treatments stimulated mitochondrial respiration; however, OA favored an overall build-up of the mitochondrial potential, and PA evoked mitochondrial fragmentation, concomitant with an ATP-oriented metabolism. Even though PA-induced a lesser increase in LD-mitochondria proximity than OA, those LD associated with highly active mitochondria suggest that they interact mainly to fuel fatty acid oxidation and ATP synthesis (that is, metabolically “active” LD). On the contrary, OA overload seemingly stimulated LD-mitochondria interaction mainly for LD growth (thus metabolically “passive” LDs). In sum, these differences point out that OA readily accumulates in LD, likely reducing their toxicity, while PA preferably stimulates mitochondrial oxidative metabolism, which may contribute to liver damage progression.

scholarly journals High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta

2013 ◽  
Vol 305 (2) ◽  
pp. E205-E212 ◽  
Author(s):  
Francisco Visiedo ◽  
Fernando Bugatto ◽  
Viviana Sánchez ◽  
Irene Cózar-Castellano ◽  
Jose L. Bartha ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Glucose ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Glucose Levels ◽  
Triglyceride Accumulation ◽  
Triglyceride Content ◽  
Low Glucose ◽  
Cpt I

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ∼30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ∼20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ∼40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ∼70% and phosphorylation levels of acetyl-CoA carboxylase by ∼25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides.

3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement

2009 ◽  
Vol 296 (3) ◽  
pp. E497-E502 ◽  
Author(s):  
A. Lombardi ◽  
P. de Lange ◽  
E. Silvestri ◽  
R. A. Busiello ◽  
A. Lanni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Atp Synthesis ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Amp Activated Protein Kinase

Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-l-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1 h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+104%), palmitoylcarnitine (+80%), or succinate (+30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to 1) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis (“proton leak”), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders.

Abstract 15465: Upregulation of Mitochondrial Atpase Inhibitory Factor 1 Mediates Increased Glycolysis in Pathological Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Bo Zhou ◽  
Arianne Caudal ◽  
Xiaoting Tang ◽  
Juan D Chavez ◽  
Andrew Keller ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Cardiac Hypertrophy ◽  
Fatty Acid Oxidation ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Inhibitory Factor ◽  
Acid Oxidation ◽  
Mitochondrial Atpase ◽  
Inhibitory Factor 1

Background: During the development of heart failure cardiac fuel metabolism switches from predominantly fatty acid oxidation (FAO) to increased reliance on glucose, especially glycolysis. Mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. We recently demonstrated that increased glucose metabolism is required for cardiomyocytes growth during pathological remodeling. Hypothesis: Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) in hypertrophied hearts suppresses ATP synthesis and shifts cardiac metabolism from fatty acid oxidation towards glucose metabolism. Methods and Results: We report that ATPIF1 expression is upregulated in cardiomyocytes and mouse hearts undergoing pathological hypertrophy. Using genetic models of ATPIF1 gain- and loss-of-function in cardiomyocytes and in mouse hearts,we find that upregulation of ATPIF1 in cardiac hypertrophy inhibits ATP synthesis. Furthermore, quantitative analysis of chemical crosslinking by mass spectrometry revealed that increased expression of ATPIF1 promoted the formation of F o F 1 -ATP synthase nonproductive tetramer. Impairment of F o F 1 -ATP synthase function in respiring mitochondria increasedROS generation resulting in transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the switch to glycolysis in pressure overload induced cardiac hypertrophy. Conclusions: We show that upregulation of ATPIF1 drives glucose metabolism at the expense of energy supply during the pathological growth of cardiomyocytes. Our study proposes a central role of ATP synthase in toggling anabolic and catabolic metabolism during pathological remodeling, illustrating a new concept for metabolic reprogramming of the heart.

Pharmacological Inhibition of Fatty Acid Oxidation as a Novel Therapeutic Concept for Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3779-3779
Author(s):  
Michael Andreeff ◽  
Michael Fiegl ◽  
Marina Konopleva ◽  
Borys Korchin ◽  
Kumar Kaluarachchi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Stromal Cells ◽  
Warburg Effect ◽  
Atp Synthesis ◽  
Leukemia Cells ◽  
Acid Oxidation ◽  
Mitochondrial Uncoupling ◽  
Therapeutic Concept ◽  
The Warburg Effect

Abstract Abstract 3779 Poster Board III-715 Otto Warburg proposed that the origin of cancer cells was closely linked to a permanent respiratory defect that bypassed the Pasteur effect, i.e. the inhibition of anaerobic fermentation by oxygen. We have recently demonstrated in leukemia cells that mitochondrial uncoupling, i.e. the abrogation of ATP synthesis in response to mitochondrial membrane potential (MMP), promotes the Warburg effect, contributes to chemo-resistance and represents a metabolic shift to fatty acid oxidation (FAO). Exposure of leukemic cells to marrow-derived mesenchymal stromal cells (MSC) promotes accumulation of lactate and reduces MMP. Stroma/leukemia co-cultures protect leukemia cells from chemotherapy-induced apoptosis. We found that he decrease in MMP was mediated by mitochondrial uncoupling accompanied by increased expression of mitochondrial uncoupling protein (UCP2) (Cancer Res. 68:5198,2008). We therefore proposed that the Warburg effect may be the result of preferential oxidation of fatty acids in cancer cell mitochondria (Cancer Res.69:2163,2009). Here we demonstrate that leukemia cells uncouple FAO from ATP synthesis, and that pharmacological inhibition of FAO with etomoxir or ranolazine inhibits proliferation and sensitizes leukemia cells – cultured alone or on bone marrow stromal cells – to apoptosis induction by the BH3 mimetic ABT-737 and the MDM-2 antagonist Nutlin 3a. Results suggest that leukemia cells rely, at least in part, on de novo fatty acid synthesis (FAS) to support FAO. Furthermore, treatment with the FAS inhibitor orlistat sensitized leukemia cells to apoptosis induction by ABT-737. Mechanistically, mitochondria derived from etomoxir treated leukemia cells were sensitized to release of cytochrome C and apoptosis-inducing-factor (AIF) upon treatment with ABT-737. Etomoxir (EX) facilitated the formation of Bak oligomers after treatment with ABT-737 suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Lastly, we present evidence that EX, in combination with liposomal ABT-737 or cytosine arabinoside (AraC), provides significant therapeutic benefit in a murine model of human leukemia (luciferase/GFP marked MOLT13 cells) as evidenced by reduced in vivo growth kinetics (BLI) and prolonged median survival (ABT-737 vs. EX+ABT-737, p=<0.05; AraC vs.EX+AraC,p<0.0001 ). Conclusions: 1) results support the notion that the Warburg effect may be the result of preferential oxidation of fatty acids by leukemia mitochondria. 2) Inhibition of fatty acid oxidation is proposed as a novel therapeutic concept for hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

STUDIES OF FATTY ACID OXIDATION: 5. THE EFFECT OF DECANOIC ACID ON OXIDATIVE PHOSPHORYLATION

1956 ◽  
Vol 34 (1) ◽  
pp. 1227-1232 ◽  
Author(s):  
P. G. Scholefield
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Rat Brain ◽  
Fatty Acid Oxidation ◽  
Rat Kidney ◽  
Atp Synthesis ◽  
Decanoic Acid ◽  
Brain Mitochondria ◽  
Acid Oxidation ◽  
Rat Brain Mitochondria

The effects of potassium decanoate on the phosphorylation associated with the oxidation of pyruvate by rat-kidney and rat-brain mitochondria have been investigated. The suggestion that these two processes may be uncoupled from each other in the presence of decanoate has been confirmed. Further, it has been shown that the decanoate-insensitive oxidation of pyruvate by rat-brain mitochondria, occurring in the absence of such stimulating agents as fumarate, is not associated with ATP synthesis. The fumarate-stimulated oxidation of pyruvate by rat-brain mitochondria, which is inhibited by decanoate, is associated with a phosphorylation process which is uncoupled by decanoate. When pyruvate oxidation by rat-kidney or by rat-brain mitochondria is uncoupled from phosphorylation, the extent of uncoupling is proportional to the amount of decanoate added.

Highly Active Antiretroviral Therapy Does Not Affect Mitochondrial β-Oxidation of Fatty Acids: An in Vitro Study in Fibroblasts

2008 ◽  
Vol 11 (1) ◽  
pp. 35-38
Author(s):  
Yasmeen M. Butt ◽  
Samira A. Kamrudin ◽  
Dinesh Rakheja
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Antiretroviral Therapy ◽  
Pregnant Women ◽  
Highly Active Antiretroviral Therapy ◽  
Culture Media ◽  
Antiretroviral Drugs ◽  
Acid Oxidation ◽  
Highly Active

Preeclampsia is a multifactorial pregnancy-specific disease. In some cases, severe preeclampsia and related disorders of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, low platelets syndrome are associated with inherited defects in mitochondrial β-oxidation of fatty acids, especially a deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD). Recently, an unexplained increase in the incidence of preeclampsia has been documented in human immunodeficiency virus (HIV)–infected pregnant women on treatment with highly active antiretroviral therapy (HAART). We performed this study to determine if antiretroviral drugs affect mitochondrial β-oxidation fatty acids in vitro. Two normal and 1 heterozygous LCHAD-deficient cell lines were exposed to up to 5 times the therapeutic concentrations of the following antiretroviral drugs: nevirapine, didanosine, lamivudine, and a combination of nelfinavir, zidovudine, and lamivudine. One homozygous LCHAD-deficient cell line served as the positive control. After exposure of the fibroblasts to these drugs for periods ranging from 2 to 10 days, accumulations of even-chain 3-hydroxy fatty acids (3-OH-C6 to 3-OH-C18) in the culture media were measured by stable-isotope dilution gas chromatography/mass spectrometry. Compared to the respective unexposed fibroblasts, there was no significant build-up of 3-hydroxy fatty acids in the culture media of normal or heterozygous LCHAD-deficient fibroblasts exposed to antiretroviral drugs. Our results show that the commonly used antiretroviral drugs do not adversely affect fatty acid oxidation in fibroblasts. Therefore, an altered fatty acid oxidation may not be the mechanism for the reported increased risk of preeclampsia in HIV-infected pregnant women on HAART.

scholarly journals The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis

2008 ◽  
Vol 295 (1) ◽  
pp. H185-H196 ◽  
Author(s):  
John J. Lehman ◽  
Sihem Boudina ◽  
Natasha Hausler Banke ◽  
Nandakumar Sambandam ◽  
Xianlin Han ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Atp Synthesis ◽  
Lipid Homeostasis ◽  
Acid Oxidation ◽  
Metabolic Efficiency ◽  
Transcriptional Coactivator ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Myocardial Fibers

High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1α (PGC-1α−/− mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1α is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1α−/− mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-l-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1α−/− mice compared with PGC-1α+/+ controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1α−/− mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1α−/− fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1α−/− mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. 13C NMR revealed that hearts from PGC-1α−/− mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during β-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1α−/− mice relative to PGC-1α+/+ following a fast. Overall, these results demonstrate that PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.

scholarly journals Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

2021 ◽  
Vol 22 (19) ◽  
pp. 10688
Author(s):  
Anna Wiśniewska ◽  
Aneta Stachowicz ◽  
Katarzyna Kuś ◽  
Magdalena Ulatowska-Białas ◽  
Justyna Totoń-Żurańska ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Therapeutic Potential ◽  
Liver Steatosis ◽  
Western Diet ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Cholesterol Ratio ◽  
Triglyceride Accumulation

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

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