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Cell Metabolism Apr 2023The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8 T cell (CTL) mitochondrial...
The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8 T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.
Topics: Linoleic Acid; CD8-Positive T-Lymphocytes; Signal Transduction
PubMed: 36898381
DOI: 10.1016/j.cmet.2023.02.013 -
Advances in Nutrition (Bethesda, Md.) May 2013
Review
Topics: Age Factors; Diet; Female; Food; Humans; Linoleic Acid; Male; Recommended Dietary Allowances; Research; United States
PubMed: 23674797
DOI: 10.3945/an.113.003772 -
Developmental Cell Dec 2022De novo beige adipocyte biogenesis involves the proliferation of progenitor cells in white adipose tissue (WAT); however, what regulates this process remains unclear....
De novo beige adipocyte biogenesis involves the proliferation of progenitor cells in white adipose tissue (WAT); however, what regulates this process remains unclear. Here, we report that in mouse models but also in human tissues, WAT lipolysis-derived linoleic acid triggers beige progenitor cell proliferation following cold acclimation, β3-adrenoceptor activation, and burn injury. A subset of adipocyte progenitors, as marked by cell surface markers PDGFRα or Sca1 and CD81, harbored cristae-rich mitochondria and actively imported linoleic acid via a fatty acid transporter CD36. Linoleic acid not only was oxidized as fuel in the mitochondria but also was utilized for the synthesis of arachidonic acid-derived signaling entities such as prostaglandin D. Oral supplementation of linoleic acid was sufficient to stimulate beige progenitor cell proliferation, even under thermoneutral conditions, in a CD36-dependent manner. Together, this study provides mechanistic insights into how diverse pathophysiological stimuli, such as cold and burn injury, promote de novo beige fat biogenesis.
Topics: Humans; Animals; Mice; Linoleic Acid; Adipose Tissue, Beige; Cell Proliferation
PubMed: 36473459
DOI: 10.1016/j.devcel.2022.11.007 -
Nutrients Feb 2019Obesity and its comorbidities, including type 2 diabetes and cardiovascular disease, are straining our healthcare system, necessitating the development of novel... (Review)
Review
Obesity and its comorbidities, including type 2 diabetes and cardiovascular disease, are straining our healthcare system, necessitating the development of novel strategies for weight loss. Lifestyle modifications, such as exercise and caloric restriction, have proven effective against obesity in the short term, yet obesity persists because of the high predilection for weight regain. Therefore, alternative approaches to achieve long term sustainable weight loss are urgently needed. Conjugated linoleic acid (CLA), a fatty acid found naturally in ruminant animal food products, has been identified as a potential anti-obesogenic agent, with substantial efficacy in mice, and modest efficacy in obese human populations. Originally described as an anti-carcinogenic fatty acid, in addition to its anti-obesogenic effects, CLA has now been shown to possess anti-atherosclerotic properties. This review summarizes the pre-clinical and human studies conducted using CLA to date, which collectively suggest that CLA has efficacy against cancer, obesity, and atherosclerosis. In addition, the potential mechanisms for the many integrative physiological effects of CLA supplementation will be discussed in detail, including an introduction to the gut microbiota as a potential mediator of CLA effects on obesity and atherosclerosis.
Topics: Atherosclerosis; Humans; Linoleic Acid; Neoplasms; Obesity
PubMed: 30754681
DOI: 10.3390/nu11020370 -
Prostaglandins, Leukotrienes, and... Dec 2021The consumption of linoleic acid (LA, ω-6 18:2), the most common ω-6 polyunsaturated fatty acid (PUFA) in the Modern Western diet (MWD), has significantly increased... (Review)
Review
The consumption of linoleic acid (LA, ω-6 18:2), the most common ω-6 polyunsaturated fatty acid (PUFA) in the Modern Western diet (MWD), has significantly increased over the last century in tandem with unprecedented incidence of chronic metabolic diseases like obesity and type 2 diabetes mellitus (T2DM). Although an essential fatty acid for health, LA was a very rare fatty acid in the diet of humans during their evolution. While the intake of other dietary macronutrients (carbohydrates like fructose) has also risen, diets rich in ω-6 PUFAs have been promoted in an effort to reduce cardiovascular disease despite unclear evidence as to how increased dietary LA consumption could promote a proinflammatory state and affect glucose metabolism. Current evidence suggests that sex, genetics, environmental factors, and disease status can differentially modulate how LA influences insulin sensitivity and peripheral glucose uptake as well as insulin secretion and pancreatic beta-cell function. Therefore, the aim of this review will be to summarize recent additions to our knowledge to refine the unique physiological and pathophysiological roles of LA in the regulation of glucose homeostasis.
Topics: Diet, Western; Female; Glucose; Homeostasis; Humans; Insulin Resistance; Insulin Secretion; Linoleic Acid; Male; Risk Factors; Sex Characteristics
PubMed: 34763302
DOI: 10.1016/j.plefa.2021.102366 -
Prostaglandins & Other Lipid Mediators Sep 2016The modern Western diet has been consumed in developed English speaking countries for the last 50 years, and is now gradually being adopted in Eastern and developing... (Review)
Review
The modern Western diet has been consumed in developed English speaking countries for the last 50 years, and is now gradually being adopted in Eastern and developing countries. These nutrition transitions are typified by an increased intake of high linoleic acid (LA) plant oils, due to their abundance and low price, resulting in an increase in the PUFA n-6:n-3 ratio. This increase in LA above what is estimated to be required is hypothesised to be implicated in the increased rates of obesity and other associated non-communicable diseases which occur following a transition to a modern Westernised diet. LA can be converted to the metabolically active arachidonic acid, which has roles in inducing inflammation and adipogenesis, and endocannabinoid system regulation. This review aims to address the possible implications of excessive LA and its metabolites in the pathogenesis of obesity.
Topics: Animals; Dietary Fats, Unsaturated; Humans; Linoleic Acid; Obesity
PubMed: 27350414
DOI: 10.1016/j.prostaglandins.2016.06.003 -
International Journal of Molecular... Dec 2020The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to... (Review)
Review
The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women's ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.
Topics: Arachidonic Acid; Female; Humans; Linoleic Acid; Pregnancy; Pregnancy Complications; Reproduction
PubMed: 33348841
DOI: 10.3390/ijms21249628 -
Nutrients Jul 2023The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists... (Review)
Review
The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists controversy regarding whether the amount of LA currently consumed in the standard American diet supports human health. The goal of this narrative review is to explore the mechanisms that underlie the hypothesis that excessive LA intake may harm human health. While LA is considered to be an essential fatty acid and support health when consumed in modest amounts, an excessive intake of LA leads to the formation of oxidized linoleic acid metabolites (OXLAMs), impairments in mitochondrial function through suboptimal cardiolipin composition, and likely contributes to many chronic diseases that became an epidemic in the 20th century, and whose prevalence continues to increase. The standard American diet comprises 14 to 25 times more omega-6 fatty acids than omega-3 fatty acids, with the majority of omega-6 intake coming from LA. As LA consumption increases, the potential for OXLAM formation also increases. OXLAMs have been associated with various illnesses, including cardiovascular disease, cancer, and Alzheimer's disease, among others. Lowering dietary LA intake can help reduce the production and accumulation of OXLAMs implicated in chronic diseases. While there are other problematic components in the standard American diet, the half-life of LA is approximately two years, which means the damage can be far more persistent than other dietary factors, and the impact of reducing excessive LA intake takes time. Therefore, additional research-evaluating approaches to reduce OXLAM formation and cardiolipin derangements following LA consumption are warranted.
Topics: Humans; Linoleic Acid; Cardiolipins; Chronic Disease; Diet
PubMed: 37513547
DOI: 10.3390/nu15143129 -
Animal Health Research Reviews Jun 2000
Review
Topics: Animal Feed; Animals; Chromatography, Gas; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Humans; Isomerism; Linoleic Acid; Meat; Neoplasms; Safety
PubMed: 11706843
DOI: 10.1017/s1466252300000049 -
Biochimie Jan 2014Linoleic acid is the most abundant polyunsaturated fatty acid in human nutrition and represents about 14 g per day in the US diet. Following the discovery of its... (Review)
Review
Linoleic acid is the most abundant polyunsaturated fatty acid in human nutrition and represents about 14 g per day in the US diet. Following the discovery of its essential functions in animals and humans in the early 1920's, studies are currently questioning the real requirement of linoleic acid. It seems now overestimated and creates controversy: how much linoleic acid should be consumed in a healthy diet? Beyond the necessity to redefine the dietary requirement of linoleic acid, many questions concerning the consequences of its excessive consumption on human health arise. Linoleic acid is a direct precursor of the bioactive oxidized linoleic acid metabolites. It is also a precursor of arachidonic acid, which produces pro-inflammatory eicosanoids and endocannabinoids. A majority of the studies on linoleic acid and its derivatives show a direct/indirect link with inflammation and metabolic diseases. Many authors claim that a high linoleic acid intake may promote inflammation in humans. This review tries to (i) highlight the importance of reconsidering the actual requirement of linoleic acid (ii) point out the lack of knowledge between dietary levels of linoleic acid and the molecular mechanisms explaining its physiological roles (iii) demonstrate the relevance of carrying out further human studies on the single variable linoleic acid.
Topics: Animals; Arachidonic Acid; Endocannabinoids; Humans; Inflammation Mediators; Linoleic Acid; Lipid Metabolism; Nutritional Requirements
PubMed: 23900039
DOI: 10.1016/j.biochi.2013.07.012