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Cell Chemical Biology May 2022The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is...
The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fatty acids by fatty acid desaturase 2 (FADS2). Genetic depletion and ectopic expression experiments show FADS2 is a key determinant of cellular sensitivity to ferroptosis. Inhibiting FADS2 markedly enhances HCV replication, whereas the ferroptosis-inducing compound erastin alters conformation of the HCV replicase and sensitizes it to direct-acting antiviral agents targeting the viral protease. Our results identify FADS2 as a rate-limiting factor in ferroptosis, and suggest the possibility of pharmacologically manipulating the ferroptosis pathway to attenuate viral replication.
Topics: Antiviral Agents; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Ferroptosis; Hepacivirus; Hepatitis C, Chronic; Humans; Iron; Permissiveness; Virus Replication
PubMed: 34520742
DOI: 10.1016/j.chembiol.2021.07.022 -
Lipids in Health and Disease Oct 2023Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws... (Review)
Review
Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws little attention. MA is distributed in various normal tissues and can be converted to several specific lipid mediators by lipoxygenase and cyclooxygenase. Recent pathological and epidemiological studies on MA raise the possibility of its effects on inflammation, cancer, dermatitis and cystic fibrosis, suggesting it is an endogenous multifunctional PUFA. This review summarizes the biosynthesis, presence, metabolism and physiological roles of MA and its relation to various diseases, as well as the significance of MA in PUFA metabolism.
Topics: Humans; Fatty Acids, Unsaturated; 8,11,14-Eicosatrienoic Acid; Inflammation
PubMed: 37838679
DOI: 10.1186/s12944-023-01937-6 -
Biomedicines Oct 2022The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid...
The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.
PubMed: 36289802
DOI: 10.3390/biomedicines10102540 -
Journal, Genetic Engineering &... Mar 2022Omega-9 fatty acids represent one of the main mono-unsaturated fatty acids (MUFA) found in plant and animal sources. They are synthesized endogenously in humans, though... (Review)
Review
BACKGROUND
Omega-9 fatty acids represent one of the main mono-unsaturated fatty acids (MUFA) found in plant and animal sources. They are synthesized endogenously in humans, though not fully compensating all body requirements. Consequently, they are considered as partially essential fatty acids. MUFA represent a healthier alternative to saturated animal fats and have several health benefits, including anti-inflammatory and anti-cancer characters. This review capitalizes on the major omega-9 pharmacological activities in context of inflammation management for its different natural forms in different dietary sources. The observed anti-inflammatory effects reported for oleic acid (OA), mead acid, and erucic acid were directed to attenuate inflammation in several physiological and pathological conditions such as wound healing and eye inflammation by altering the production of inflammatory mediators, modulating neutrophils infiltration, and altering VEGF effector pathway. OA action mechanisms as anti-tumor agent in different cancer types are compiled for the first time based on its anti- and pro-carcinogenic actions.
CONCLUSION
We conclude that several pathways are likely to explain the anti-proliferative activity of OA including suppression of migration and proliferation of breast cancer cells, as well stimulation of tumor suppressor genes. Such action mechanisms warrant for further supportive clinical and epidemiological studies to confirm the beneficial outcomes of omega-9 consumption especially over long-term intervention.
PubMed: 35294666
DOI: 10.1186/s43141-022-00329-0 -
Frontiers in Molecular Biosciences 2023Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse...
Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.
PubMed: 36825199
DOI: 10.3389/fmolb.2023.1097955 -
Clinical Science (London, England :... Dec 2022Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid...
Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.
Topics: Humans; Animals; Swine; Cystic Fibrosis; Fatty Acids; Ferrets; Phospholipids; Docosahexaenoic Acids; Linoleic Acids
PubMed: 36416119
DOI: 10.1042/CS20220450 -
Nutrients Apr 2023Malnutrition is prevalent in low-middle-income countries (LMICs), but it is usually clinically diagnosed through abnormal anthropometric parameters characteristic of... (Review)
Review
Malnutrition is prevalent in low-middle-income countries (LMICs), but it is usually clinically diagnosed through abnormal anthropometric parameters characteristic of protein energy malnutrition (PEM). In doing so, other contributors or byproducts of malnutrition, notably essential fatty acid deficiency (EFAD), are overlooked. Previous research performed mainly in high-income countries (HICs) shows that deficiencies in essential fatty acids (EFAs) and their -3 and -6 polyunsaturated fatty acid (PUFA) byproducts (also known as highly unsaturated fatty acids or HUFAs) lead to both abnormal linear growth and impaired cognitive development. These adverse developmental outcomes remain an important public health issue in LMICs. To identify EFAD before severe malnutrition develops, clinicians should perform blood fatty acid panels to measure levels of fatty acids associated with EFAD, notably Mead acid and HUFAs. This review demonstrates the importance of measuring endogenous fatty acid levels for measuring fatty acid intake in various child populations in LMICs. Featured topics include a comparison of fatty acid levels between global child populations, the relationships between growth and cognition and PUFAs and the possible mechanisms driving these relationships, and the potential importance of EFAD and HUFA scores as biomarkers of overall health and normal development.
Topics: Humans; Child; Fatty Acids; Fatty Acids, Essential; Fatty Acids, Unsaturated; alpha-Linolenic Acid; Malnutrition; Cognition; Fatty Acids, Omega-3
PubMed: 37111152
DOI: 10.3390/nu15081933 -
Public Health Nutrition Apr 2022To quantify PUFA-associated improvement in linear growth among children aged 6-10 years.
OBJECTIVE
To quantify PUFA-associated improvement in linear growth among children aged 6-10 years.
DESIGN
Serum fatty acids (FA), including essential FA (EFA) (linoleic acid (LA) and α-linolenic acid (ALA)) were quantified at baseline using GC-MS technology. FA totals by class (n-3, n-6, n-9, PUFA and SFA) and FA ratios were calculated. Height-for-age Z-score (HAZ) relative to WHO population reference values were calculated longitudinally at baseline, 6 and 12 months. Linear regression models estimated PUFA, HIV status and their interaction-associated standardised mean difference (SMD) and 95 % CI in HAZ over 12 months.
SETTING
Community controls and children connected to community health centre in Kampala, Uganda, were enrolled.
PARTICIPANTS
Children perinatally HIV-infected (CPHIV, n 82), or HIV-exposed but uninfected (CHEU, n 76) and community controls (n 78).
RESULTS
Relative to highest FA levels, low SFA (SMD = 0·31, 95 % CI: 0·03, 0·60), low Mead acid (SMD = 0·38, 95 % CI: 0·02, 0·74), low total n-9 (SMD = 0·44, 95 % CI: 0·08, 0·80) and low triene-to-tetraene ratio (SMD = 0·42, 95 % CI: 0·07, 0·77) predicted superior growth over 12 months. Conversely, low LA (SMD = -0·47, 95 % CI: -0·82, -0·12) and low total PUFA (sum of total n-3, total n-6 and Mead acid) (SMD = -0·33 to -0·39, 95 % CI: -0·71, -0·01) predicted growth deficit over 12 months follow-up, regardless of HIV status.
CONCLUSION
Low n-3 FA (ALA, EPA and n-3 index) predicted growth deficits among community controls. EFA sufficiency may improve stature in school-aged children regardless of HIV status. Evaluating efficacy of diets low in total SFA, sufficient in EFA and enriched in n-3 FA for improving child growth is warranted.
PubMed: 35369893
DOI: 10.1017/S1368980022000611 -
Public Health Nutrition Apr 2020To measure fatty acid composition, particularly whole-blood PUFA content, in acutely malnourished children and identify associations with markers of nutritional and...
OBJECTIVE
To measure fatty acid composition, particularly whole-blood PUFA content, in acutely malnourished children and identify associations with markers of nutritional and health status.
DESIGN
PUFA were assessed in dried blood spots obtained from a cross-sectional study. Nutritional and health status were assessed by anthropometry, haemoglobinopathies, inflammation and blood counts.
SETTING
Cambodia.
PARTICIPANTS
The study was conducted with 174 children aged 0·5-18 years with acute malnutrition.
RESULTS
Among total fatty acids (FA), the relative percentage of total PUFA was 20 % FA, with 14 % of the children having very low PUFA (mead acid (MA):arachidonic acid (AA) >0·02, n-6 docosapentaenoic acid:DHA >0·2 and total n-6:n-3 PUFA >10·5). Wasting was not associated with any PUFA. Stunting and low height were consistently positively associated with total PUFA and positively with n-6 PUFA. Height was positively associated with n-3 long-chain PUFA (LCPUFA). The presence of haemoglobinopathies or inflammation was positively associated with MA:AA, but not total PUFA. Elevated blood platelet counts were positively correlated with linoleic acid and appeared to be influenced by anaemia (P = 0·010) and inflammation (P = 0·002). Monocyte counts were high during inflammation (P = 0·052) and correlated positively with n-6 LCPUFA and n-3 LCPUFA.
CONCLUSIONS
Children with acute malnutrition or stunting had low PUFA, while elevated platelets and monocytes were associated with high PUFA. In acutely malnourished children, inflammation could lead to elevated blood cell counts resulting in increased whole-blood PUFA which does not reflect dietary intake or nutritional status.
Topics: Adolescent; Anthropometry; Body Mass Index; Cambodia; Child; Child Nutrition Disorders; Child, Preschool; Cross-Sectional Studies; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Growth Disorders; Health Status; Humans; Infant; Male; Nutritional Status; Wasting Syndrome
PubMed: 31973779
DOI: 10.1017/S1368980019003744 -
JPEN. Journal of Parenteral and Enteral... Aug 2019Intravenous fish oil (FO) treats pediatric intestinal failure-associated liver disease (IFALD). There are concerns that a lipid emulsion composed of ω-3 fatty acids...
BACKGROUND
Intravenous fish oil (FO) treats pediatric intestinal failure-associated liver disease (IFALD). There are concerns that a lipid emulsion composed of ω-3 fatty acids will cause an essential fatty acid deficiency (EFAD). This study's objective was to quantify the risk for abnormal fatty acid concentrations in children treated with FO.
METHODS
Inclusion criteria for this prospective study were children with intestinal failure. Intravenous soybean oil (SO) was replaced with FO for no longer than 6 months. Serum fatty acids were analyzed using linear and logistic models, and compared with age-based norms to determine the percentage of subjects with low and high concentrations.
RESULTS
Subjects (n = 17) started receiving FO at a median of 3.6 months (interquartile range 2.4-9.6 months). Over time, α-linolenic, linoleic, arachidonic, and Mead acid decreased, whereas docosahexaenoic and eicosapentaenoic acid increased (P < 0.001 for all). Triene-tetraene ratios remained unchanged (P = 1). Although subjects were 1.8 times more likely to develop a low linoleic acid while receiving FO vs SO (95% CI: 1.4-2.3, P < 0.01), there was not a significant risk for low arachidonic acid. Subjects were 1.6 times more likely to develop high docosahexaenoic acid while receiving FO vs SO; however, this was not significant (95% CI: 0.9-2.6, P = 0.08).
CONCLUSION
In this cohort of parenteral nutrition-dependent children, switching from SO to FO led to a decrease in essential fatty acid concentrations, but an EFAD was not evident. Low and high levels of fatty acids developed. Further investigation is needed to clarify if this is clinically significant.
Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fat Emulsions, Intravenous; Fatty Acids; Fatty Acids, Essential; Fatty Acids, Omega-3; Female; Fish Oils; Humans; Infant; Intestinal Diseases; Linoleic Acid; Liver Diseases; Male; Parenteral Nutrition; Prospective Studies; Soybean Oil
PubMed: 30900274
DOI: 10.1002/jpen.1532