Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake andDe NovoFatty Acid Synthesis

A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD) anddb/dbandob/obmice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers. By echocardiography, ejection fraction (EF) and fractional shortening (FS) of left ventricular diameter during systole were significantly reduced. TheVmaxfor saturable fatty acid uptake was increased and significantly correlated with cardiac triglycerides and insulin concentrations.Vmaxalso correlated with expression of genes for the cardiac fatty acid transportersCd36andSlc27a1. Genes forde novofatty acid synthesis (Fasn, Scd1) were also upregulated. Ten oxidative phosphorylation pathway genes were downregulated, suggesting that a decrease in cardiomyocyte ATP synthesis might explain the decreased contractile function in obese hearts.

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Alternative pathway of free fatty acid uptake from phospholipids and upregulation of de novo fatty acid synthesis in lipoprotein lipase-deficient murine adipose tissue

Atherosclerosis Supplements ◽

10.1016/s1567-5688(02)80369-5 ◽

2002 ◽

Vol 3 (2) ◽

pp. 145

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Lipoprotein Lipase ◽

Fatty Acid Synthesis ◽

De Novo ◽

Alternative Pathway ◽

Acid Synthesis ◽

Fatty Acid Uptake ◽

Acid Uptake

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00032.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. E205-E212 ◽

Cited By ~ 45

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.

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Macrophage metabolism in the intestine is compartment-specific and regulated by the microbiota

10.1101/2021.06.24.449804 ◽

2021 ◽

Author(s):

Nicholas A Scott ◽

Melissa Lawson ◽

Ryan Hodgetts ◽

Lindsay J Hall ◽

Elizabeth Mann

Keyword(s):

Fatty Acid ◽

Amino Acid ◽

Amino Acid Uptake ◽

Acid Synthesis ◽

Fatty Acid Uptake ◽

Vital Role ◽

Antibiotic Administration ◽

Acid Uptake ◽

Large Neutral Amino Acid ◽

Metabolic Functions

Intestinal macrophages play a vital role in the maintenance of gut homeostasis through signals derived from the microbiota. We previously demonstrated that microbial-derived metabolites can shape the metabolic functions of macrophages. Here, we show that antibiotic-induced disruption of the intestinal microbiota dramatically alters both the local metabolite environment, and the metabolic functions of macrophages in the colon. Broad-spectrum antibiotic administration in mice increased expression of the large neutral amino acid transporter and accordingly, amino acid uptake. Subsequently, antibiotic administration enhanced the metabolic functions of colonic macrophages, increasing phosphorylation of components of mammalian/mechanistic target of rapamycin (mTOR) signalling pathways, increasing expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increasing mitochondrial function and increased levels of ECAR and OCR as a direct measure of glycolysis and OXPHOS. Small bowel macrophages were less metabolically active than in the colon, with macrophage metabolism being independent of the microbiota. Finally, we reveal tissue resident Tim4+ CD4+ macrophages exhibit enhanced fatty acid uptake alongside reduced fatty acid synthesis compared to their recruited counterparts. Thus the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for functions when monocyte recruitment and macrophage differentiation.

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Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00169.2015 ◽

2015 ◽

Vol 309 (5) ◽

pp. L435-L440 ◽

Cited By ~ 23

Author(s):

Brian B. Graham ◽

Rahul Kumar ◽

Claudia Mickael ◽

Linda Sanders ◽

Liya Gebreab ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Fatty Acid ◽

Right Ventricle ◽

Fatty Acid Uptake ◽

Left Ventricular ◽

Acid Uptake ◽

Substrate Uptake ◽

Severe Pulmonary Hypertension ◽

Metabolic Substrate ◽

Sequential Administration

In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[18F]fluoroglucose (18F-FDG) and 14-(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in 18F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in 18F-FTHA uptake (−2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake.

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Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

10.1101/417949 ◽

2018 ◽

Cited By ~ 6

Author(s):

Elena Panzilius ◽

Felix Holstein ◽

Jonas Dehairs ◽

Mélanie Planque ◽

Christine von Toerne ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Cell Density ◽

De Novo ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Oncogenic Signaling ◽

Key Enzyme ◽

Low Cell Density

AbstractFerroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.

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Decreased Myocardial Free Fatty Acid Uptake in Patients With Idiopathic Dilated Cardiomyopathy: Evidence of Relationship With Insulin Resistance and Left Ventricular Dysfunction

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2006.06.005 ◽

2006 ◽

Vol 12 (8) ◽

pp. 644-652 ◽

Cited By ~ 68

Author(s):

Helena Tuunanen ◽

Erik Engblom ◽

Alexandru Naum ◽

Mika Scheinin ◽

Kjell Någren ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Free Fatty Acid ◽

Dilated Cardiomyopathy ◽

Left Ventricular Dysfunction ◽

Ventricular Dysfunction ◽

Fatty Acid Uptake ◽

Left Ventricular ◽

Idiopathic Dilated Cardiomyopathy ◽

Acid Uptake

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Free fatty acids as a determinant of myocardial oxygen consumption: a caveat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y81-119 ◽

1981 ◽

Vol 59 (8) ◽

pp. 806-810 ◽

Cited By ~ 2

Author(s):

Gilles R. Dagenais ◽

Jacques R. Rouleau ◽

Isabelle Côté

Keyword(s):

Blood Flow ◽

Oxygen Consumption ◽

Fatty Acid ◽

Myocardial Oxygen Consumption ◽

Flow Distribution ◽

Fatty Acid Uptake ◽

Left Ventricular ◽

Acid Uptake ◽

Blood Flow Distribution ◽

Isoproterenol Infusion

The present study was designed to determine whether the antilipolytic agent β-pyridylcarbinol modifies left ventricular blood flow distribution. It has been shown that the administration of this agent during isoproterenol infusion reduced both myocardial oxygen consumption and myocardial free fatty acid uptake. Although attributed to a decrease in myocardial free fatty acid uptake, the reduction in myocardial oxygen consumption might also be due to a modification in left ventricular blood flow distribution induced by β-pydidyiearbinol. To verify this possibility left ventricular blood flow distribution was measured with radioactive microspheres in 10 anesthetized dogs during control, during an infusion of isoproterenol (0.2 μg∙kg−1∙min−1) alone, and during an isoproterenol plus β-pyridylcarbinol infusion (0.1 mg∙kg−1∙min−1). In comparison with the control observations, isoproterenol infusion induced a significant increase of 37% in heart rate and of nearly 100% in myocardial free fatty acid uptake, myocardial oxygen consumption, and coronary blood flow, but did not affect the left ventricular blood flow distribution. The addition of β-pyridylcarbinol to the isoproterenol infusion did not cause any significant changes in left ventricular blood flow distribution, although it reduced myocardial free fatty acid uptake by 67% (p < 0.01). Despite this reduction, myocardial oxygen consumption did not change. However, in dogs with a myocardial oxygen uptake above 12.5 mL∙min−1∙100 g−1 during isoproterenol infusion, there was a reduction in myocardial oxygen consumption when β-pyridylcarbinol was added, without significant change in left ventricular blood flow distribution. The present findings reveal that β-pyridylcarbinol does not modify left ventricular blood flow distribution and that the determinant role of free fatty acids on myocardial oxygen consumption is restricted to conditions with increased myocardial demand.

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Differences in transport of fatty acids and expression of fatty acid transporting proteins in adipose tissue of obese black and white women

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00194.2005 ◽

2006 ◽

Vol 290 (1) ◽

pp. E87-E91 ◽

Cited By ~ 24

Author(s):

Joseph F. Bower ◽

Julianne M. Davis ◽

Enhui Hao ◽

Hisham A. Barakat

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Fatty Acid ◽

African American Women ◽

White Women ◽

De Novo ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Omental Adipose Tissue ◽

Protein Levels

We have reported that the rate of de novo triglyceride (TG) synthesis by omental, but not subcutaneous, adipose tissue was higher in African-American women (AAW) than in Caucasian women (CAW). The purpose of this study was to explore the potential mechanisms underlying this increase. Toward that end, we determined the activities of key enzymes in the pathway of TG synthesis, the rates of uptake of fatty acids by adipocytes, mRNA and protein levels of the fatty acid-transporting proteins FAT/CD36 and FATP, and mRNA and protein levels of PPARγ in omental fat of AAW and CAW. The results showed 1) no difference in the activity of phosphofructokinase, glycerol-3-phosphate dehydrogenase, or diacylglycerol acyltransferase; 2) a higher rate of fatty acid uptake by adipocytes of the AAW; 3) an increase in the mRNA and protein levels of CD36 and FATP4 in the fat of the AAW; and 4) an increase in the mRNA and protein levels of PPARγ, which can stimulate the expression of CD36 and FATP. These results suggest that the increase in the transport of fatty acid, which is mediated by the overexpression of the transport proteins in the omental adipose tissue of the AAW, might contribute to the higher prevalence of obesity in AAW.

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