Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase

2011 ◽  
Vol 435 (3) ◽  
pp. 723-732 ◽  
Author(s):  
Xuefei Gao ◽  
Kuai Li ◽  
Xiaoyan Hui ◽  
Xiangping Kong ◽  
Gary Sweeney ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Physiological Role ◽  
Carnitine Palmitoyltransferase ◽  
Acid Uptake ◽  
Pharmacological Inhibition

The adipocyte is the principal cell type for fat storage. CPT1 (carnitine palmitoyltransferase-1) is the rate-limiting enzyme for fatty acid β-oxidation, but the physiological role of CPT1 in adipocytes remains unclear. In the present study, we focused on the specific role of CPT1A in the normal functioning of adipocytes. Three 3T3-L1 adipocyte cell lines stably expressing hCPT1A (human CPT1A) cDNA, mouse CPT1A shRNA (short-hairpin RNA) or GFP (green fluorescent protein) were generated and the biological functions of these cell lines were characterized. Alteration in CPT1 activity, either by ectopic overexpression or pharmacological inhibition using etomoxir, did not affect adipocyte differentiation. However, overexpression of hCPT1A significantly reduced the content of intracellular NEFAs (non-esterified fatty acids) compared with the control cells when adipocytes were challenged with fatty acids. The changes were accompanied by an increase in fatty acid uptake and a decrease in fatty acid release. Interestingly, CPT1A protected against fatty acid-induced insulin resistance and expression of pro-inflammatory adipokines such as TNF-α (tumour necrosis factor-α) and IL-6 (interleukin-6) in adipocytes. Further studies demonstrated that JNK (c-Jun N terminal kinase) activity was substantially suppressed upon CPT1A overexpression, whereas knockdown or pharmacological inhibition of CPT1 caused a significant enhancement of JNK activity. The specific inhibitor of JNK SP600125 largely abolished the changes caused by the shRNA- and etomoxir-mediated decrease in CPT1 activity. Moreover, C2C12 myocytes co-cultured with adipocytes pre-treated with fatty acids displayed altered insulin sensitivity. Taken together, our findings have identified a favourable role for CPT1A in adipocytes to attenuate fatty acid-evoked insulin resistance and inflammation via suppression of JNK.

scholarly journals FSMP-15. EVALUATING THE ROLE OF LONG-CHAIN FATTY ACID METABOLISM IN PROMOTING GLIOBLASTOMA GROWTH

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i19-i19
Author(s):  
Divya Ravi ◽  
Carmen del Genio ◽  
Haider Ghiasuddin ◽  
Arti Gaur
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Survival Rate ◽  
Tumor Progression ◽  
Acid Synthesis ◽  
Normal Brain ◽  
Acid Uptake ◽  
Exogenous Fatty Acid ◽  
Long Chain

Abstract Glioblastomas (GBM) or Stage IV gliomas, are the most aggressive of primary brain tumors and are associated with high mortality and morbidity. Patients diagnosed with this lethal cancer have a dismal survival rate of 14 months and a 5-year survival rate of 5.6% despite a multimodal therapeutic approach, including surgery, radiation therapy, and chemotherapy. Aberrant lipid metabolism, particularly abnormally active de novo fatty acid synthesis, is recognized to have a key role in tumor progression and chemoresistance in cancers. Previous studies have reported a high expression of fatty acid synthase (FASN) in patient tumors, leading to multiple investigations of FASN inhibition as a treatment strategy. However, none of these have developed as efficacious therapies. Furthermore, when we profiled FASN expression using The Cancer Genome Atlas (TCGA) we determined that high FASN expression in GBM patients did not confer a worse prognosis (HR: 1.06; p-value: 0.51) and was not overexpressed in GBM tumors compared to normal brain. Therefore, we need to reexamine the role of exogenous fatty acid uptake over de novofatty acid synthesis as a potential mechanism for tumor progression. Our study aims to measure and compare fatty acid oxidation (FAO) of endogenous and exogenous fatty acids between GBM patients and healthy controls. Using TCGA, we have identified the overexpression of multiple enzymes involved in mediating the transfer and activation of long-chain fatty acids (LCFA) in GBM tumors compared to normal brain tissue. We are currently conducting metabolic flux studies to (1) assess the biokinetics of LCFA degradation and (2) establish exogenous versus endogenous LCFA preferences between patient-derived primary GBM cells and healthy glial and immune cells during steady state and glucose-deprivation.

scholarly journals Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

2010 ◽  
Vol 298 (6) ◽  
pp. E1122-E1130 ◽  
Author(s):  
Sun Ju Choi ◽  
Francis Kim ◽  
Michael W. Schwartz ◽  
Brent E. Wisse
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Cell Lines ◽  
Saturated Fatty Acids ◽  
Neuronal Cell ◽  
Acid Exposure ◽  
Inflammatory Signaling ◽  
Hypothalamic Neurons

Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1–7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFα, as judged by induction of IκBα (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IκBα protein, and TNFα pretreatment reduced insulin-mediated p-Akt activation by 30% ( P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 μM for ≤6 h) nor palmitate exposure alone (200 μM for ≤24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.

scholarly journals Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure

2015 ◽  
Vol 308 (4) ◽  
pp. C297-C307 ◽  
Author(s):  
Veronika Franekova ◽  
Yeliz Angin ◽  
Nicole T. H. Hoebers ◽  
Will A. Coumans ◽  
Peter J. Simons ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Acid Uptake ◽  
Omega 3 ◽  
Rat Cardiomyocytes ◽  
Metabolic Remodeling ◽  
High Insulin

Insulin resistance is an important risk factor for the development of several cardiac pathologies, thus advocating strategies for restoring insulin sensitivity of the heart in these conditions. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), have been shown to improve insulin sensitivity in insulin-sensitive tissues, but their direct effect on insulin signaling and metabolic parameters in the myocardium has not been reported previously. The aim of this study was therefore to examine the ability of EPA and DHA to prevent insulin resistance in isolated rat cardiomyocytes. Primary rat cardiomyocytes were made insulin resistant by 48 h incubation in high insulin (HI) medium. Parallel incubations were supplemented by 200 μM EPA or DHA. Addition of EPA or DHA to the medium prevented the induction of insulin resistance in cardiomyocytes by preserving the phosphorylation state of key proteins in the insulin signaling cascade and by preventing persistent relocation of fatty acid transporter CD36 to the sarcolemma. Only cardiomyocytes incubated in the presence of EPA, however, exhibited improvements in glucose and fatty acid uptake and cell shortening. We conclude that ω-3 PUFAs protect metabolic and functional properties of cardiomyocytes subjected to insulin resistance-evoking conditions.

scholarly journals Circulating fatty acid profiles are associated with protein energy wasting in maintenance hemodialysis patients: a cross-sectional study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ban-Hock Khor ◽  
◽  
Sharmela Sahathevan ◽  
Ayesha Sualeheen ◽  
Mohammad Syafiq Md Ali ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Nutritional Status ◽  
Serum Albumin ◽  
Saturated Fatty Acids ◽  
Maintenance Hemodialysis ◽  
Model Assessment ◽  
Cross Sectional ◽  
Markers Of Inflammation

AbstractThe metabolic impact of circulating fatty acids (FAs) in patients requiring hemodialysis (HD) is unknown. We investigated the associations between plasma triglyceride (TG) FAs and markers of inflammation, insulin resistance, nutritional status and body composition. Plasma TG-FAs were measured using gas chromatography in 341 patients on HD (age = 55.2 ± 14.0 years and 54.3% males). Cross-sectional associations of TG-FAs with 13 markers were examined using multivariate linear regression adjusted for potential confounders. Higher levels of TG saturated fatty acids were associated with greater body mass index (BMI, r = 0.230), waist circumference (r = 0.203), triceps skinfold (r = 0.197), fat tissue index (r = 0.150), serum insulin (r = 0.280), and homeostatic model assessment of insulin resistance (r = 0.276), but lower malnutrition inflammation score (MIS, r =  − 0.160). Greater TG monounsaturated fatty acid levels were associated with lower lean tissue index (r =  − 0.197) and serum albumin (r =  − 0.188), but higher MIS (r = 0.176). Higher levels of TG n-3 polyunsaturated fatty acids (PUFAs) were associated with lower MIS (r =  − 0.168) and interleukin-6 concentrations (r =  − 0.115). Higher levels of TG n-6 PUFAs were associated with lower BMI (r =  − 0.149) but greater serum albumin (r = 0.112). In conclusion, TG monounsaturated fatty acids were associated with poor nutritional status, while TG n-3 PUFAs were associated with good nutritional status. On the other hand, TG saturated fatty acids and TG n-6 PUFAs had both favorable and unfavorable associations with nutritional parameters.

scholarly journals Evaluation of Chemical Variability of Cured Vanilla Beans (Vanilla tahitensis and Vanilla planifolia)

2009 ◽  
Vol 4 (10) ◽  
pp. 1934578X0900401 ◽  
Author(s):  
Christel Brunschwig ◽  
François Xavier Collard ◽  
Jean-Pierre Bianchini ◽  
Phila Raharivelomanana
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Dry Matter ◽  
Monounsaturated Fatty Acids ◽  
Vanilla Planifolia ◽  
Chemical Variability ◽  
Total Fatty Acids ◽  
Curing Method ◽  
Fatty Acid Compositions

In order to establish a chemical fingerprint of vanilla diversity, thirty samples of V. planifolia J. W. Moore and V. tahitensis G. Jackson cured beans from seven producing countries were examined for their aroma and fatty acid contents. Both fatty acid and aroma compositions were found to vary between vanilla species and origins. Vanillin was found in higher amounts in V. planifolia (1.7-3.6% of dry matter) than in V. tahitensis (1.0-2.0%), and anisyl compounds were found in lower amounts in V. planifolia (0.05%) than in V. tahitensis (1.4%-2.1%). Ten common and long chain monounsaturated fatty acids (LCFA) were identified and were found to be characteristic of the vanilla origin. LCFA derived from secondary metabolites have discriminating compositions as they reach 5.9% and 15.8% of total fatty acids, respectively in V. tahitensis and V. planifolia. This study highlights the role of the curing method as vanilla cured beans of two different species cultivated in the same country were found to have quite similar fatty acid compositions.

scholarly journals Lipid Accumulation and Chronic Kidney Disease

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 722 ◽  
Author(s):  
Zhibo Gai ◽  
Tianqi Wang ◽  
Michele Visentin ◽  
Gerd Kullak-Ublick ◽  
Xianjun Fu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Scavenger Receptor ◽  
Fatty Acid Uptake ◽  
Lipid Lowering ◽  
Fatty Acid Transport ◽  
Acid Uptake

Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced β-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.

Caprenin 1. Digestion, Absorption, and Rearrangement in Thoracic Duct-Cannulated Rats

1991 ◽  
Vol 10 (3) ◽  
pp. 325-340 ◽  
Author(s):  
D. R. Webb ◽  
R. A. Sanders
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Female Rats ◽  
Acid Uptake ◽  
Long Chain Fatty Acids ◽  
Male And Female ◽  
Medium Chain ◽  
Male And Female Rats ◽  
Long Chain ◽  
Chain Fatty Acids

Caprenin (CAP) is a triglyceride that primarily contains caprylic (C8:0), capric (C10:0), and behenic (C22:0) acids. This study was undertaken to determine whether or not CAP is qualitatively digested, absorbed, and rearranged like other dietary fats and oils that contain these medium-chain and very long-chain fatty acids. In vitro results showed that neat CAP, coconut oil (CO) and peanut oil (PO) were hydrolyzed by porcine pancreatic lipase. All of the neat triglycerides also were digested in vivo by both male and female rats. This was shown by the recovery of significantly more extractable lymphatic fat than with fat-free control animals and by the recovery of orally administered triglyceride-derived fatty acids in lymph triglycerides. However, substantially more PO (74%) and CO (51%) were recovered in lymph relative to CAP (10%). These quantitative differences are consistent with the fatty acid composition of each triglyceride and primary routes of fatty acid uptake. The 24-h lymphatic recovery of CAP-derived C8:0, C10:0, and C22:0 averaged 3.9%, 17.8%, and 11.2%, respectively, for male and female rats. The C8:0 and C10:0 results approximated those obtained with CO (2.0% and 16.3%, respectively). In contrast, the 24-h absorbability of C22:0 in CAP was significantly less than that seen in PO (55.4%). Finally, there was no evidence of significant rearrangement of the positions of fatty acids on glycerol during digestion and absorption. Those fatty acids recovered in lymphatic fat tended to occupy the same glyceride positions that they did in the neat administered oils. However, the lymph fats recovered from all animals dosed with fat emulsions were enriched with endogenous lymph fatty acids. It is concluded that CAP is qualitatively digested, absorbed, and processed like any dietary fat or oil that contains medium-chain and very long-chain fatty acids.

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