CLOCK Gene Variation Is Associated with the Incidence of Metabolic Syndrome Modulated by Monounsaturated Fatty Acids.
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ABSTRACT:
SUBMITTER: Shin D
PROVIDER: S-EPMC8156860 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDisruption of the circadian system may be causal for manifestations of the metabolic syndrome (MetS).ObjectiveThe objective was to study the associations of 5 CLOCK polymorphisms with MetS features by analyzing fatty acid (FA) composition from dietary and red blood cell (RBC) membrane sources.DesignParticipants (n = 1100) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Anthropometric and biochemical measurements and genotypes were determined. Postprandial lipids and the FA composition of RBC membranes were analyzed.ResultsCLOCK single nucleotide polymorphisms were significantly associated with obesity and individual components of MetS. For single nucleotide polymorphism rs4580704, minor allele carriers had a 46% lower risk of hypertension than did noncarriers. The monounsaturated fatty acid (MUFA) content of RBC membranes, particularly oleic acid, changed according to CLOCK genetic variants (P < 0.05). We identified significant gene-diet interactions associated with MetS at the CLOCK locus. By dichotomizing MUFA intake, we found different effects across rs4580704 genotypes for glucose (P = 0.020) and insulin resistance (P = 0.026). The protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was >13.2% of energy. We also found different effects across CLOCK 3111T-->C genotypes for saturated fatty acid intake (% of energy) (P = 0.017). The deleterious effect of gene variants on waist circumference was only found with high saturated fatty acid intakes (>11.8%).ConclusionsCLOCK polymorphisms interact with FAs to modulate MetS traits. The dietary source and membrane content of MUFAs are implicated in the relations between alterations in the circadian system and MetS.
| S-EPMC2777463 | biostudies-literature
Project description:Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown.We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2±5.2 years) in the Cardiovascular Health Study (CHS; 1992-2006) and 3577 middle-aged adults (mean age, 54.1±5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987-2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003-2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95% confidence interval, 1.02-1.76) and 1.57 (95% confidence interval, 1.11-2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95% confidence interval, 1.23-2.50) and 1.92 (95% confidence interval, 1.22-3.03) for 24:1, respectively (P for trend ?0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard.Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.
| S-EPMC3717970 | biostudies-literature
Project description:Intake of monounsaturated fatty acids has been reported to reduce oxidative stress, insulin resistance and related inflammatory processes and may thus protect from skin photoaging. The objective of this study was to investigate the association between the risk of photoaging, monounsaturated fatty acids intake and the sources of monounsaturated fatty acids.A cross sectional study was conducted within the framework of the SUVIMAX cohort. The survey included 1264 women and 1655 men aged between 45 and 60 years old. Dietary monounsaturated fatty acids intakes were estimated by dietary source through at least ten 24-h diet records completed during the first 2.5 years of the follow-up period. Severity of facial skin photoaging was graded by trained investigators at baseline during a clinical examination using a 6-grade scale illustrated by photographs. A lower risk of severe photoaging was associated with higher intakes of monounsaturated fatty acids from olive oil in both sexes. Strikingly, no association was found with intake of monounsaturated fatty acids from animal sources whether from dairy products, meat or processed meat.These findings support the beneficial effect of dietary olive oil or healthy diet habits associated with olive oil consumption on the severity of facial photoaging.
| S-EPMC3435270 | biostudies-literature
Project description:The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.
| S-EPMC6430697 | biostudies-literature
Project description:Evidence regarding the relationship of n-3 fatty acids (FA) to type 2 diabetes and metabolic syndrome components (MetS) is inconsistent.To examine associations of adipose tissue n-3 FA with MetS.We studied 1611 participants without prior history of diabetes or heart disease who were participants in a population-based case-control study of diet and heart disease (The Costa Rica Heart Study). We calculated prevalence ratios (PR) and 95% confidence intervals (CI) for MetS by quartile of n-3 FA in adipose tissue derived mainly from plants (?-Linolenic acid (ALA)), fish (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) or metabolism (docosapentaenoic acid (DPA), as well as the EPA:ALA ratio, a surrogate marker of delta-6 desaturase activity).N-3 FA levels in adipose tissue were associated with MetS prevalence in opposite directions. The PR (95% CI) for the highest compared with the lowest quartile adjusted for age, sex, body mass index (BMI), residence, lifestyle, diet and other FAs were 0.60 (0.44, 0.81) for ALA, 1.43 (1.12, 1.82) for EPA, 1.63 (1.22, 2.18) for DPA and 1.47 (1.14, 1.88) for EPA:ALA, all P for trend <0.05. Although these associations were no longer significant (except DPA) after adjustment for BMI, ALA and DPA were associated with lower glucose and higher triglyceride levels, P<0.05 (respectively).These results suggest that ALA could exert a modest protective benefit, whereas EPA and DHA are not implicated in MetS. The positive associations for DPA and MetS could reflect higher delta-6 desaturase activity caused by increased adiposity.
| S-EPMC4286455 | biostudies-literature
Project description:Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single-nucleotide polymorphisms (SNPs), -11377C>G and -11391G>A, on metabolic-related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the -11391A allele (P = 0.001) but lower for the -11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the -11391G>A SNP. Carriers of the -11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the -11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P-interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (> or =13% of energy intake), -11391A carriers had lower BMI (27.1 kg/m(2) for GA+AA vs. 29.1 kg/m(2) for GG, P = 0.002) and decreased obesity risk (odds ratio for -11391A = 0.52, 95% confidence interval (CI); 0.28-0.96; P = 0.031). However, we did not detect genotype-related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between the -11391G>A SNPs and obesity-related traits and the potential to moderate such effects using dietary modification.
| S-EPMC2753535 | biostudies-literature
Project description:BackgroundMonounsaturated fatty acids (MUFAs) are the best components for biodiesel when considering the low temperature fluidity and oxidative stability. However, biodiesel derived from vegetable oils or microbial lipids always consists of significant amounts of polyunsaturated and saturated fatty acids (SFAs) alkyl esters, which hampers its practical applications. Therefore, the fatty acid composition should be modified to increase MUFA contents as well as enhancing oil and lipid production.ResultsThe model microorganism Escherichia coli was engineered to produce free MUFAs. The fatty acyl-ACP thioesterase (AtFatA) and fatty acid desaturase (SSI2) from Arabidopsis thaliana were heterologously expressed in E. coli BL21 star(DE3) to specifically release free unsaturated fatty acids (UFAs) and convert SFAs to UFAs. In addition, the endogenous fadD gene (encoding acyl-CoA synthetase) was disrupted to block fatty acid catabolism while the native acetyl-CoA carboxylase (ACCase) was overexpressed to increase the malonyl coenzyme A (malonyl-CoA) pool and boost fatty acid biosynthesis. The finally engineered strain BL21?fadD/pE-AtFatAssi2&pA-acc produced 82.6 mg/L free fatty acids (FFAs) under shake-flask conditions and FFAs yield on glucose reached about 3.3% of the theoretical yield. Two types of MUFAs, palmitoleate (16:1?9) and cis-vaccenate (18:1?11) made up more than 75% of the FFA profiles. Fed-batch fermentation of this strain further enhanced FFAs production to a titer of 1.27 g/L without affecting fatty acid compositions.ConclusionsThis study demonstrated the possibility to regulate fatty acid composition by using metabolic engineering approaches. FFAs produced by the recombinant E. coli strain consisted of high-level MUFAs and biodiesel manufactured from these fatty acids would be more suitable for current diesel engines.
| S-EPMC4021618 | biostudies-literature
Project description:Metabolic extremes provide opportunities to understand enzymatic and metabolic plasticity and biotechnological tools for novel biomaterial production. We discovered that seed oils of many Thunbergia species contain up to 92% of the unusual monounsaturated petroselinic acid (18:1Δ6), one of the highest reported levels for a single fatty acid in plants. Supporting the biosynthetic origin of petroselinic acid, we identified a Δ6-stearoyl-acyl carrier protein (18:0-ACP) desaturase from Thunbergia laurifolia, closely related to a previously identified Δ6-palmitoyl-ACP desaturase that produces sapienic acid (16:1Δ6)-rich oils in Thunbergia alata seeds. Guided by a T. laurifolia desaturase crystal structure obtained in this study, enzyme mutagenesis identified key amino acids for functional divergence of Δ6 desaturases from the archetypal Δ9-18:0-ACP desaturase and mutations that result in nonnative enzyme regiospecificity. Furthermore, we demonstrate the utility of the T. laurifolia desaturase for the production of unusual monounsaturated fatty acids in engineered plant and bacterial hosts. Through stepwise metabolic engineering, we provide evidence that divergent evolution of extreme petroselinic acid and sapienic acid production arises from biosynthetic and metabolic functional specialization and enhanced expression of specific enzymes to accommodate metabolism of atypical substrates.
| S-EPMC9335243 | biostudies-literature
Project description:Obesity induces numerous physiological changes that can impact cancer risk and patient response to therapy. Obese patients with cervical cancer have been reported to have superior outcomes following chemoradiotherapy, suggesting that free fatty acids (FFA) might enhance response to radiotherapy. Here, using preclinical models, we show that monounsaturated and diunsaturated FFAs (uFFA) radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARγ and p53 to promote lipid uptake, storage, and metabolism after radiotherapy. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiotherapy, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate suppressed tumor growth in xenografts after radiotherapy, an effect that could be partially mimicked in tumors from high fat diet-induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiotherapy, particularly in p53 wild-type tumors.SignificanceMetabolism of monounsaturated and diunsaturated fatty acids improves the efficacy of radiotherapy in cancer through modulation of p53 activity. See related commentary by Jungles and Green, p. 4513.
| S-EPMC9772149 | biostudies-literature
Project description:Obesity is a recognized epidemic worldwide, and the accumulation of excess free saturated fatty acids (SFAs) in cells induces cellular lipotoxic damage and increases the risk of a wide spectrum of metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat SFA-induced cellular damage. However, the comparative studies of the two types of unsaturated fatty acids (UFAs) are still limited. We investigated the effects of different MUFAs and PUFAs in the human hepatocyte line L-02 cells in vitro, and in high-fat-diet (HFD)-induced obese C57BL/6 mice in vivo. The results of the in vitro study showed that SFAs induced significant cellular lipotoxic damage, but the combination of MUFAs/PUFAs with SFAs significantly improved the impaired cell viability. Particularly, oleic acid (OA) was superior to eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachidonic acid (AA) in terms of its anti-apoptotic effect and inhibition of endoplasmic reticulum (ER) stress. In vivo, both olive-oil-enriched (HFD + OO) and fish-oil-enriched high-fat diets (HFD + FO) reduced hepatic steatosis and improved insulin sensitivity in obese mice. However, FO induced an abnormal increase in serum aspartate aminotransferase (AST) and an increase in the oxidative stress indicator Malondialdehyde (MDA). Liver-targeted lipidomic analysis showed that liver lipid metabolites under the two types of UFA dietary interventions differed from the HFD group, modulating the abundance of some lipid metabolites such as triglycerides (TGs) and glycerophospholipids. Furthermore, the FO diet significantly increased the abundance of the associated FA 20:5 long-chain lipid metabolites, whereas the OO diet regulated the unsaturation of all fatty acids in general and increased the abundance of FA 18:1 in the overall lipid metabolites, especially TGs, which may primarily contribute to the FO, and OO drove protection in NAFLD.
| S-EPMC10386220 | biostudies-literature