scholarly journals Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Teresa Manzo ◽  
Boone M. Prentice ◽  
Kristin G. Anderson ◽  
Ayush Raman ◽  
Aislyn Schalck ◽  
...  
Keyword(s):  
Fatty Acids ◽  
T Cells ◽  
Lipid Metabolism ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Metabolic Reprogramming ◽  
Long Chain Fatty Acids ◽  
Cell Functions ◽  
Long Chain ◽  
Chain Fatty Acids

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

Effects of cold acclimation on lipid metabolism in adipose tissue

1961 ◽  
Vol 200 (4) ◽  
pp. 847-850 ◽  
Author(s):  
Judith K. Patkin ◽  
E. J. Masoro
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cold Acclimation ◽  
Long Chain Fatty Acids ◽  
Synthetic Capacity ◽  
And Control ◽  
Long Chain ◽  
Chain Fatty Acids

Cold acclimation is known to alter hepatic lipid metabolism. Liver slices from cold-acclimated rats have a greatly depressed capacity to synthesize long-chain fatty acids from acctate-1-C14. Since adipose tissue is the major site of lipogenic activity in the intact animal, its fatty acid synthetic capacity was studied. In contrast to the liver, it was found that adipose tissue from the cold-acclimated rat synthesized three to six times as much long-chain fatty acids per milligram of tissue protein as the adipose tissue from the control rat living at 25°C. Evidence is presented indicating that adipose tissue from cold-acclimated and control rats esterify long-chain fatty acids at the same rate. The ability of adipose tissue to oxidize palmitic acid to CO2 was found to be unaltered by cold acclimation. The fate of the large amount of fatty acid synthesized in the adipose tissue of cold-acclimated rats is discussed.

scholarly journals Fine metabolic regulation in ruminants via nutrient–gene interactions: saturated long-chain fatty acids increase expression of genes involved in lipid metabolism and immune response partly through PPAR-α activation

2011 ◽  
Vol 107 (2) ◽  
pp. 179-191 ◽  
Author(s):  
Massimo Bionaz ◽  
Betsy J. Thering ◽  
Juan J. Loor
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Metabolic Regulation ◽  
Target Genes ◽  
Long Chain Fatty Acids ◽  
Response Data ◽  
Expression Of Genes ◽  
Gene Network Analysis ◽  
Long Chain ◽  
Chain Fatty Acids

Madin–Darby Bovine Kidney cells cultured with 150 μm of Wy-14 643 (WY, PPARα agonist) or twelve long-chain fatty acids (LCFA; 16 : 0, 18 : 0, cis-9–18 : 1, trans-10–18 : 1, trans-11–18 : 1, 18 : 2n-6, 18 : 3n-3, cis-9, trans-11–18 : 2, trans-10, cis-12–18 : 2, 20 : 0, 20 : 5n-3 and 22 : 6n-3) were used to uncover PPAR-α target genes and determine the effects of LCFA on expression of thirty genes with key functions in lipid metabolism and inflammation. Among fifteen known PPAR-α targets in non-ruminants, ten had greater expression with WY, suggesting that they are bovine PPAR-α targets. The expression of SPP1 and LPIN3 was increased by WY, with no evidence of a similar effect in the published literature, suggesting that both represent bovine-specific PPAR-α targets. We observed the strongest effect on the expression of PPAR-α targets with 16 : 0, 18 : 0 and 20 : 5n-3.When considering the overall effect on expression of the thirty selected genes 20 : 5n-3, 16 : 0 and 18 : 0 had the greatest effect followed by 20 : 0 and c9t11–18 : 2. Gene network analysis indicated an overall increase in lipid metabolism by WY and all LCFA with a central role of PPAR-α but also additional putative transcription factors. A greater increase in the expression of inflammatory genes was observed with 16 : 0 and 18 : 0. Among LCFA, 20 : 5n-3, 16 : 0 and 18 : 0 were the most potent PPAR-α agonists. They also affected the expression of non-PPAR-α targets, eliciting an overall increase in the expression of genes related to lipid metabolism, signalling and inflammatory response. Data appear to highlight a teleological evolutionary adaptation of PPAR in ruminants to cope with the greater availability of saturated rather than unsaturated LCFA.

scholarly journals Effect of unsaturated C18 fatty acids (oleic, linoleic and α-linolenic acids) on ruminal fermentation and production of fatty acids isomers in artificial rumen

2008 ◽  
Vol 52 (No. 3) ◽  
pp. 87-94 ◽  
Author(s):  
D. Jalc ◽  
M. Certik ◽  
K. Kundrikova ◽  
P. Namestkova
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Rumen Fluid ◽  
Rumen Fermentation ◽  
Long Chain Fatty Acids ◽  
Ruminal Fermentation ◽  
Trans Isomers ◽  
Stabilization Period ◽  
Long Chain ◽  
Chain Fatty Acids

The objective of this study was to examine the effect of oleic (OA), linoleic (LA) and &alpha;-linolenic (ALA) acid used as supplements (3.5% wt/wt) to a diet containing 80% lucerne and 20% barley on rumen fermentation and lipid metabolism in an artificial rumen (Rusitec). The experiment lasted 12 days with 6 days of stabilization period. The fatty acid (FA) supplementation to a mixed diet did not affect any parameters of rumen fermentation (degradation of DM, NDF, ADF, total VFA production, production of acetate, propionate and butyrate). The methane production was decreased numerically (NS) by FA supplements (OA, LA, and ALA by about 8, 8.3 and 13.2%, respectively). The stoichiometric parameters of rumen fermentation such as NM (nitrogen incorporated by microflora), OMF (organic matter fermented) and EMS (efficiency of microbial protein synthesis) were affected by unsaturated C18 FA to a different extent. EMS calculated from NM and OMF was significantly (<i>P</i> < 0.01) increased by OA, ALA and decreased (<i>P</i> < 0.01) by LA. The lipid metabolism was also affected by C18 FA supplements. The concentration of total FA and proportion of LCFA (long chain fatty acids, > C<sub>18:0</sub>) increased and proportion of MCFA (medium chain fatty acids, C<sub>14:0</sub> &minus; C<sub>17:0</sub>) decreased after OA, LA and ALA addition. The biohydrogenation (BH) of fatty acids was characterized by increased (NS) accumulation of stearic acid and trans isomers C18:1 and lower SFA/UFA ratio in the effluent. The concentrations of two main BH intermediates, TVA (trans 11 C<sub>18:1</sub>) and CLA (cis 9, trans 11 C<sub>18:2</sub>), significantly (<i>P</i> < 0.001) increased (TVA &minus; 1.06, 1.29 and 1.10; CLA &minus; 0.32, 0.43 and 0.36 mg/g rumen fluid DM, respectively) after OA, LA and ALA supplementation compared to the control (TVA &minus; 0.7; CLA &minus; 0.23).

Transcriptional regulation of bovine elongation of very long chain fatty acids protein 6 in lipid metabolism and adipocyte proliferation

2019 ◽  
Vol 120 (8) ◽  
pp. 13932-13943 ◽  
Author(s):  
Zainaguli Junjvlieke ◽  
Chu‐Gang Mei ◽  
Rajwali Khan ◽  
Wen‐Zhen Zhang ◽  
Jie‐Yun Hong ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Transcriptional Regulation ◽  
Lipid Metabolism ◽  
Long Chain Fatty Acids ◽  
Long Chain ◽  
Chain Fatty Acids

scholarly journals Differential Effects of Fatty Acid Saturation and Chain Length on NASH in Juvenile Iberian Pigs

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 682-682 ◽  
Author(s):  
Kayla Dillard ◽  
Morgan Coffin ◽  
Gabriella Hernandez ◽  
Victoria Smith ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Body Weight ◽  
Fatty Acid ◽  
Liver Injury ◽  
Olive Oil ◽  
Coconut Oil ◽  
Long Chain Fatty Acids ◽  
Medium Chain ◽  
Long Chain ◽  
Chain Fatty Acids

Abstract Objectives Non-alcoholic fatty liver disease (NAFLD) represents the major cause of pediatric chronic liver pathology in the United States. The objective of this study was to compare the relative effect of inclusion of isocaloric amounts of saturated medium-chain fatty acids (hydrogenated coconut oil), saturated long-chain fatty acids (lard) and unsaturated long-chain fatty acids (olive oil) on endpoints of NAFLD and insulin resistance. Methods Thirty-eight 15-d-old Iberian pigs were fed 1 of 4 diets containing (g/kg body weight × d) 1) control (CON; n = 8): 0 g fructose, 10.5 g fat, and 187 kcal metabolizable energy (ME), 2) lard (LAR; n = 10): 21.6 g fructose, 17.1 g fat (100% lard) and 299 kcal ME, 3) hydrogenated coconut oil (COCO; n = 10): 21.6 g fructose, 16.9 g fat (42.5% lard and 57.5% coconut oil) and 299 kcal ME, and 4) olive oil (OLV, n = 10): 21.6 g fructose, 17.1 g fat (43.5% lard and 56.5% olive oil) and 299 kcal ME, for 9 consecutive weeks. Body weight was recorded every 3 d. Serum markers of liver injury and dyslipidemia were measured on d 60 at 2 h post feeding, with all other serum measures assessed on d 70. Liver tissue was collected on d 70 for histology, triacylglyceride (TG) quantification, and metabolomics analysis. Results Tissue histology indicated the presence of steatosis in LAR, COCO and OLV compared with CON (P ≤ 0.001), with a further increase in in non-alcoholic steatohepatitis (NASH) in OLV and COCO compared with LAR (P ≤ 0.01). Alanine and aspartate aminotransferases were higher in COCO and OLV (P ≤ 0.01) than CON. All treatment groups had lower liver concentrations of methyl donor's choline and betaine versus CON, while bile acids were differentially changed (P ≤ 0.05). COCO had higher levels of TGs with less carbons (Total carbons &lt; 52) than all other groups (P ≤ 0.05). Several long-chain acylcarnitines involved in fat oxidation were higher in OLV versus all other groups (P ≤ 0.05). Conclusions Inclusion of fats enriched in medium-chain saturated and long-chain unsaturated fatty acids in a high-fructose high-fat diet increased liver injury, compared with fats with a long-chain saturated fatty acid profile. Further research is required to investigate the mechanisms causing this difference in physiological response to these dietary fat sources. Funding Sources ARI, AcornSeekers.

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