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American Journal of Clinical Dermatology Jan 2021Our understanding of the pathogenesis of acne vulgaris is still evolving. It is known that multiple factors impact acne pathophysiology, including genetic, hormonal,... (Review)
Review
Our understanding of the pathogenesis of acne vulgaris is still evolving. It is known that multiple factors impact acne pathophysiology, including genetic, hormonal, inflammatory, and environmental influences. Because of its implications in many of these factors, diet has been a part of the acne discussion for decades. Several studies have evaluated the significance of the glycemic index of various foods and glycemic load in patients with acne, demonstrating individuals with acne who consume diets with a low glycemic load have reduced acne lesions compared with individuals on high glycemic load diets. Dairy has also been a focus of study regarding dietary influences on acne; whey proteins responsible for the insulinotropic effects of milk may contribute more to acne development than the actual fat or dairy content. Other studies have examined the effects of omega-3 fatty acid and γ-linoleic acid consumption in individuals with acne, showing individuals with acne benefit from diets consisting of fish and healthy oils, thereby increasing omega-3 and omega-6 fatty acid intake. Recent research into the effects of probiotic administration in individuals with acne present promising results; further study of the effects of probiotics on acne is needed to support the findings of these early studies. In this review, we discuss the current evidence regarding the diets of US patients with acne and how they may impact acne and acne treatment.
Topics: Acne Vulgaris; Dairy Products; Fatty Acids, Omega-3; Feeding Behavior; Glycemic Index; Humans; Linoleic Acid; Probiotics; United States
PubMed: 32748305
DOI: 10.1007/s40257-020-00542-y -
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 -
Gut Jun 2022Altered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis of the metabolites changes in...
OBJECTIVE
Altered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis of the metabolites changes in portal venous blood and in comparison with the metabolites changes in liver tissues and stool samples of HCC patients and healthy liver donors.
DESIGN
Serum (portal and central vein), liver tissue (HCC tumour and adjacent non-tumour, normal liver) and stool samples were collected from 102 subjects (52 HCC patients and 50 healthy controls) in the discovery cohort; and 100 subjects (50 HCC patients and 50 healthy controls) in an independent validation cohort. Untargeted metabolomic profiling was performed using high-performance liquid chromatography-mass spectrometry. The function of candidate metabolites was validated in hepatocyte cell lines.
RESULTS
Detailed metabolomic evaluation showed distinct clusters of metabolites in serum, liver tissue and stool samples from patients with HCC and control individuals (p<0.001). HCC patients had significantly higher levels of portal vein serum and HCC tissue metabolites of DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide than healthy controls, which were associated with impaired liver function and poor survival. On the other hand, HCC patients had lower levels of linoleic acid and phenol in portal vein and stool samples than healthy controls. Linoleic acid and phenol significantly inhibited HCC proliferation, inferring their anti-HCC function as protective metabolites.
CONCLUSIONS
The integrative metabolome analysis of serum, tissue and stool metabolites revealed unreported metabolic alterations in HCC patients. In portal vein, we identified elevated and depleted metabolites signifying that they might play a role in HCC development.
Topics: Carcinoma, Hepatocellular; Humans; Linoleic Acid; Liver Neoplasms; Metabolome; Metabolomics; Phenols; Portal Vein
PubMed: 34344785
DOI: 10.1136/gutjnl-2021-325189 -
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 -
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 -
BMC Medicine Jun 2022Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA...
Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants.
BACKGROUND
Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization.
METHODS
We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis).
RESULTS
GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol.
CONCLUSIONS
We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.
Topics: Biological Specimen Banks; Cardiovascular Diseases; Cholesterol, LDL; Fatty Acids; Fatty Acids, Unsaturated; Genome-Wide Association Study; Humans; Ischemic Stroke; Linoleic Acid; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; United Kingdom
PubMed: 35692035
DOI: 10.1186/s12916-022-02399-w -
Nature Mar 2021The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells. This process requires major molecular...
The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA), a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.
Topics: Adult; Aged; Aging; Animals; Cell Self Renewal; Cells, Cultured; Chaperone-Mediated Autophagy; Energy Metabolism; Female; Glycolysis; Hematopoietic Stem Cells; Humans; Linoleic Acid; Male; Mice; Middle Aged; Multiple Myeloma; Rejuvenation; Young Adult
PubMed: 33442062
DOI: 10.1038/s41586-020-03129-z -
Nature Communications Sep 2019Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated...
Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites.
Topics: Adipose Tissue; Animals; Cell Line; Diet, High-Fat; Diet, Western; Dietary Fats, Unsaturated; Dietary Supplements; Energy Metabolism; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Gastrointestinal Microbiome; Humans; Inflammation; Lactobacillus; Linoleic Acid; Metabolic Diseases; Mice; Mice, Inbred C57BL; Models, Animal; Obesity; Oleic Acids
PubMed: 31488836
DOI: 10.1038/s41467-019-11978-0 -
Nature Communications Dec 2023Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic...
Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
Topics: Male; Mice; Animals; Catalase; Linoleic Acids; Linoleic Acid; Fatty Liver; Liver
PubMed: 38071367
DOI: 10.1038/s41467-023-44026-z -
Cells Jul 2022Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.
Topics: Animals; Autophagy; Cell Line, Tumor; Humans; Linoleic Acid; Lipid Droplets; Mice; Neuroblastoma; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease
PubMed: 35892594
DOI: 10.3390/cells11152297