Lipidomic profiling of the hepatic esterified fatty acid composition in diet-induced nonalcoholic fatty liver disease in genetically diverse Collaborative Cross mice.

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity.

Shark liver oil supplementation enriches endogenous plasmalogens and reduces markers of dyslipidemia and inflammation.

Plasmalogens are membrane glycerophospholipids with diverse biological functions. Reduced plasmalogen levels have been observed in metabolic diseases; hence, increasing their levels might be beneficial in ameliorating these conditions. Shark liver oil (SLO) is a rich source of alkylglycerols that can be metabolized into plasmalogens. This study was designed to evaluate the impact of SLO supplementation on endogenous plasmalogen levels in individuals with features of metabolic disease. In this randomized, double-blind, placebo-controlled cross-over study, the participants (10 overweight or obese males) received 4-g Alkyrol® (purified SLO) or placebo (methylcellulose) per day for 3 weeks followed by a 3-week washout phase and were then crossed over to 3 weeks of the alternate placebo/Alkyrol® treatment. SLO supplementation led to significant changes in plasma and circulatory white blood cell lipidomes, notably increased levels of plasmalogens and other ether lipids. In addition, SLO supplementation significantly decreased the plasma levels of total free cholesterol, triglycerides, and C-reactive protein. These findings suggest that SLO supplementation can enrich plasma and cellular plasmalogens and this enrichment may provide protection against obesity-related dyslipidemia and inflammation.

Different effects of high-fat diets rich in different oils on lipids metabolism, oxidative stress and gut microbiota.

The study aimed to investigate the different effects of high-fat (HF) diets rich in different oils on lipid metabolism, oxidative stress, and gut mirobiota. C57BL/6 mice were divided into 4 groups: (1) control group (CG) was fed with normal diet, (2) olive oil (OO) group was fed with high-fat diet containing OO, (3) lard oil (LO) group was fed with high-fat diet containing LO, (4) soybean oil (SO) group was fed with high-fat diet containing SO. After 12 weeks, serum lipids, and oxidative stress indices were analyzed. Gut microbiota analysis was carried out based on the sequencing results of 16S rRNA. High fat diet can increase serum and liver lipids and upregulate sterol regulatory element-binding protein-1c related genes expression. Serum and liver malondialdehyde (MDA) levels in LO group were significantly higher than those in CG and OO groups. In CG, the family Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Desulfovibrionaceae had the large effect sizes. HF diets resulted in the increase of Actinobacteria and Enterococcaceae abundance, and the decrease of Bacteroidetes, Proteobacteria Lactobacillales and microbiota diversity. The abundance of Actinobacteria and Lactobacillales is the link to the serum TC and MDA levels. HF diets have the harmful influence on the serum lipids, oxidative stress and endothelial function. They can also cause gut microbiota dysbiosis.

High-fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress.

High-fat (HF) diet-induced obesity precipitates multiple metabolic disorders including insulin resistance, glucose intolerance, oxidative stress, and inflammation, resulting in the initiation of cell death programs. Previously, we demonstrated murine germline knockout of calcium-independent phospholipase A2γ (iPLA2γ) prevented HF diet-induced weight gain, attenuated insulin resistance, and decreased mitochondrial permeability transition pore (mPTP) opening leading to alterations in bioenergetics. To gain insight into the specific roles of hepatic iPLA2γ in mitochondrial function and cell death under metabolic stress, we generated a hepatocyte-specific iPLA2γ-knockout (HEPiPLA2γKO). Using this model, we compared the effects of an HF diet on wild-type versus HEPiPLA2γKO mice in eicosanoid production and mitochondrial bioenergetics. HEPiPLA2γKO mice exhibited higher glucose clearance rates than WT controls. Importantly, HF-diet induced the accumulation of 12-hydroxyeicosatetraenoic acid (12-HETE) in WT liver which was decreased in HEPiPLA2γKO. Furthermore, HF-feeding markedly increased Ca2+ sensitivity and resistance to ADP-mediated inhibition of mPTP opening in WT mice. In contrast, ablation of iPLA2γ prevented the HF-induced hypersensitivity of mPTP opening to calcium and maintained ADP-mediated resistance to mPTP opening. Respirometry revealed that ADP-stimulated mitochondrial respiration was significantly reduced by exogenous 12-HETE. Finally, HEPiPLA2γKO hepatocytes were resistant to calcium ionophore-induced lipoxygenase-mediated lactate dehydrogenase release. Collectively, these results demonstrate that an HF diet increases iPLA2γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death.

Extensive transcription mis-regulation and membrane defects in AdipoR2-deficient cells challenged with saturated fatty acids.

How cells maintain vital membrane lipid homeostasis while obtaining most of their constituent fatty acids from a varied diet remains largely unknown. Here, we used transcriptomics, lipidomics, growth and respiration assays, and membrane property analyses in human HEK293 cells or human umbilical vein endothelial cells (HUVEC) to show that the function of AdipoR2 is to respond to membrane rigidification by regulating many lipid metabolism genes. We also show that AdipoR2-dependent membrane homeostasis is critical for growth and respiration in cells challenged with saturated fatty acids. Additionally, we found that AdipoR2 deficiency causes transcriptome and cell physiological defects similar to those observed in SREBP-deficient cells upon SFA challenge. Finally, we compared several genes considered important for lipid homeostasis, namely AdipoR2, SCD, FADS2, PEMT and ACSL4, and found that AdipoR2 and SCD are the most important among these to prevent membrane rigidification and excess saturation when human cells are challenged with exogenous SFAs. We conclude that AdipoR2-dependent membrane homeostasis is one of the primary mechanisms that protects against exogenous SFAs.

The C. elegans PAQR-2 and IGLR-2 membrane homeostasis proteins are uniquely essential for tolerating dietary saturated fats.

How cells maintain vital membrane lipid homeostasis while obtaining most of their constituent fatty acids from a varied diet remains largely unknown. Here, we report the first whole-organism (Caenorhabditis elegans) forward genetic screen to identify genes essential for tolerance to dietary saturated fatty acids (SFAs). We found that only the PAQR-2/IGLR-2 pathway, homologous to the human adiponectin receptor 2 (AdipoR2) pathway, is uniquely essential to prevent SFA-mediated toxicity. When provided a SFA-rich diet, worms lacking either protein accumulate an excess of SFAs in their membrane phospholipids, which is accompanied by membrane rigidification. Additionally, we used fluorescence resonance energy transfer (FRET) to show that the interaction between PAQR-2 and IGLR-2 is regulated by membrane fluidity, suggesting a mechanism by which this protein complex senses membrane properties. We also created versions of PAQR-2 that lacked parts of the cytoplasmic N-terminal domain and showed that these were still functional, though still dependent on the interaction with IGLR-2. We conclude that membrane homeostasis via the PAQR-2/IGLR-2 fluidity sensor is the only pathway specifically essential for the non-toxic uptake of dietary SFAs in C. elegans.

Bioavailability and spatial distribution of fatty acids in the rat retina after dietary omega-3 supplementation.

Spatial changes of FAs in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids (PLs), EPA-containing TGs, DHA-containing PLs, or DHA-containing TGs. Qualitative changes in FA composition of plasma, erythrocytes, and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of PC and PE species in retina were determined by LC coupled to MS/MS and MALDI coupled to MS imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that PLs as well as TGs are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain PUFAs (more than 28 carbons) following PL-EPA and TG-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of FAs in the rat retina.

Association between 12α-hydroxylated bile acids and hepatic steatosis in rats fed a high-fat diet.

High-fat (HF) diet induces hepatic steatosis that is a risk factor for noncommunicable diseases such as obesity, type 2 diabetes and cardiovascular disease. Previously, we found that HF feeding in rats increases the excretion of fecal bile acids (BAs), specifically 12α-hydroxylated (12αOH) BAs. Although the liver is the metabolic center in our body, the association between hepatic steatosis and 12αOH BAs in HF-fed rats is unclear. Thus, we investigated extensively BA composition in HF-fed rats and evaluated the association between hepatic steatosis and 12αOH BAs. Acclimated male inbred WKAH/HkmSlc rats were divided into two groups and fed either control or HF diet for 8 weeks. Feeding HF diet increased hepatic triglyceride and total cholesterol concentrations, which correlated positively with 12αOH BAs concentrations but not with non-12αOH BAs in the feces, portal plasma and liver. Accompanied by the increase in 12αOH BAs, the rats fed HF diet showed increased fat absorption and higher mRNA expression of liver Cidea. The enhancement of 12αOH BA secretion may contribute to hepatic steatosis by the promotion of dietary fat absorption and hepatic Cidea mRNA expression. The increase in 12αOH BAs was associated with enhanced liver cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) mRNA expression. There was a significant increase in 7α-hydroxycholesterol, a precursor of BAs, in the liver of HF-fed rats. Altogether, these data suggest that the HF diet increases preferentially 12αOH BAs synthesis by utilizing the accumulated hepatic cholesterol and enhancing mRNA expression of Cyp7a1 and Cyp8b1 in the liver.

Endotoxin May Not Be the Major Cause of Postprandial Inflammation in Adults Who Consume a Single High-Fat or Moderately High-Fat Meal.

BACKGROUND: Metabolic endotoxemia is considered a cause for high-fat diet (HFD)-induced inflammation. However, convincing experimental evidence in humans is scant. OBJECTIVE: We determined whether a HFD or moderately HFD increases LPS and LPS-mediated cytokine production in the postprandial blood (PPB). METHODS: Ninety-eight volunteers (age: 37.3 ± 1.5 y) from the cross-sectional phenotyping study (PS) and 62 volunteers (age: 26.8 ± 1.2 y) from the intervention study (IS) consumed a breakfast containing 60% kcal fat (HF) and 36% kcal fat (moderately HF), respectively. For the IS, only the results from the placebo group are presented. Blood samples were probed for LPS-mediated cytokine production by incubating them with LPS inhibitor polymyxin B (PMB) for 24 h at 37°C besides the Limulus amebocyte lysate (LAL) assay. Repeated-measures ANOVA was used to compare the temporal changes of metabolic profiles and treatment outcomes. RESULTS: At least 87.5% of the plasma LPS measurements in 32 PS volunteers from each time point were below the LAL assay sensitivity (0.002 EU/mL). PMB suppressed IL-1ß (P = 0.035) and IL-6 (P = 0.0487) production in the 3 h PPB of the PS after 24 h incubation at 37°C compared to the vehicle control, suggesting the presence of LPS. However, the amount of LPS did not increase the cytokine concentrations in the 3 h PPB above the fasting concentrations. Such suppression was not detected in the PPB of the IS. Treating whole blood with lipoprotein lipase (LPL) significantly (P < 0.05) increased FFA and cytokine (IL-1ß, IL-6, TNF-α) concentrations in both studies. CONCLUSION: LPS may not be the major cause of postprandial inflammation in healthy adults consuming a moderately HF meal (36% kcal fat, similar to the typical American diet) or a HF meal (60% kcal fat). Plasma FFAs may modulate postprandial inflammation. The prevailing concept of HFD-induced metabolic endotoxemia requires careful re-evaluation. The PS was registered at clinicaltrials.gov as NCT02367287 and the IS as NCT02472171.

Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury.

Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpi and Leap2) in fat-1 versus WT mice fed EtOH. fat-1 mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1 versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.

Four nights of sleep restriction suppress the postprandial lipemic response and decrease satiety.

Chronic sleep restriction, or inadequate sleep, is associated with increased risk of cardiometabolic disease. Laboratory studies demonstrate that sleep restriction causes impaired whole-body insulin sensitivity and glucose disposal. Evidence suggests that inadequate sleep also impairs adipose tissue insulin sensitivity and the NEFA rebound during intravenous glucose tolerance tests, yet no studies have examined the effects of sleep restriction on high-fat meal lipemia. We assessed the effect of 5 h time in bed (TIB) per night for four consecutive nights on postprandial lipemia following a standardized high-fat dinner (HFD). Furthermore, we assessed whether one night of recovery sleep (10 h TIB) was sufficient to restore postprandial metabolism to baseline. We found that postprandial triglyceride (TG) area under the curve was suppressed by sleep restriction (P = 0.01), but returned to baseline values following one night of recovery. Sleep restriction decreased NEFAs throughout the HFD (P = 0.02) and NEFAs remained suppressed in the recovery condition (P = 0.04). Sleep restriction also decreased participant-reported fullness or satiety (P = 0.03), and decreased postprandial interleukin-6 (P < 0.01). Our findings indicate that four nights of 5 h TIB per night impair postprandial lipemia and that one night of recovery sleep may be adequate for recovery of TG metabolism, but not for markers of adipocyte function.

High-Fat Feeding in Time-Dependent Manner Affects Metabolic Routes Leading to Nervonic Acid Synthesis in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. The disturbances in the fatty acid composition of stored lipids are more important than the lipid species itself, which may influence the overall effect caused by these molecules. Thus, uncovering time-dependent changes in the fatty acid composition of accumulated lipid fractions after a high fat diet seems to be a new marker of NAFLD occurrence. The experiments were conducted on high fat fed Wistar rats. The blood and liver samples were collected at the end of each experimental week and used to assess the content of lipid fractions and their fatty acid composition by gas liquid chromatography. The expression of proteins from lipid metabolism pathways and of fatty acid exporting proteins were detected by Western blotting. In the same high fat feeding period, decreased de novo lipogenesis, increased ß-oxidation and lipid efflux were demonstrated. The observed effects may be the first liver protective mechanisms against lipotoxicity. Nevertheless, such effects were still not sufficient to prevent the liver from proinflammatory lipid accumulation. Moreover, the changes in liver metabolic pathways caused the plasma nervonic acid concentration in sphingomyelin to decrease simultaneously with NAFLD development, which may be a steatosis occurrence prognostic marker.

DGAT2 partially compensates for lipid-induced ER stress in human DGAT1-deficient intestinal stem cells.

Dietary lipids are taken up as FAs by the intestinal epithelium and converted by diacylglycerol acyltransferase (DGAT) enzymes into triglycerides, which are packaged in chylomicrons or stored in cytoplasmic lipid droplets (LDs). DGAT1-deficient patients suffer from vomiting, diarrhea, and protein losing enteropathy, illustrating the importance of this process to intestinal homeostasis. Previously, we have shown that DGAT1 deficiency causes decreased LD formation and resistance to unsaturated FA lipotoxicity in patient-derived intestinal organoids. However, LD formation was not completely abolished in patient-derived organoids, suggesting the presence of an alternative mechanism for LD formation. Here, we show an unexpected role for DGAT2 in lipid metabolism, as DGAT2 partially compensates for LD formation and lipotoxicity in DGAT1-deficient intestinal stem cells. Furthermore, we show that (un)saturated FA-induced lipotoxicity is mediated by ER stress. More importantly, we demonstrate that overexpression of DGAT2 fully compensates for the loss of DGAT1 in organoids, indicating that induced DGAT2 expression in patient cells may serve as a therapeutic target in the future.

Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet.

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring's hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (Lpin1), a gene involved in lipid metabolism. Furthermore, DNA methylation of Lpin1 TF binding sites correlated with mRNA expression of Lpin1 These findings suggest that the effect of a prenatal HF diet on the adult offspring's metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.

Maternal Dietary Docosahexaenoic Acid Alters Lipid Peroxidation Products and (n-3)/(n-6) Fatty Acid Balance in Offspring Mice.

The abundance of docosahexaenoic acid (DHA) in the mammalian brain has generated substantial interest in the search for its roles in regulating brain functions. Our recent study with a gene/stress mouse model provided evidence to support the ability for the maternal supplement of DHA to alleviate autism-associated behavior in the offspring. DHA and arachidonic acid (ARA) are substrates of enzymatic and non-enzymatic reactions, and lipid peroxidation results in the production of 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE), respectively. In this study, we examine whether a maternal DHA-supplemented diet alters fatty acids (FAs), as well as lipid peroxidation products in the pup brain, heart and plasma by a targeted metabolite approach. Pups in the maternal DHA-supplemented diet group showed an increase in DHA and a concomitant decrease in ARA in all brain regions examined. However, significant increases in 4-HHE, and not 4-HNE, were found mainly in the cerebral cortex and hippocampus. Analysis of heart and plasma showed large increases in DHA and 4-HHE, but a significant decrease in 4-HNE levels only in plasma. Taken together, the DHA-supplemented maternal diet alters the (n-3)/(n-6) FA ratio, and increases 4-HHE levels in pup brain, heart and plasma. These effects may contribute to the beneficial effects of DHA on neurodevelopment, as well as functional changes in other body organs.

n-3 PUFAs improve erythrocyte fatty acid profile in patients with small AAA: a randomized controlled trial.

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults, which has no current drug therapy. Inflammation and abnormal redox status are believed to be key pathogenic mechanisms for AAA. In light of evidence correlating inflammation with aberrant fatty acid profiles, this study compared erythrocyte fatty acid content in 43 AAA patients (diameter 3.0-4.5 cm) and 52 healthy controls. In addition, the effect of omega-3 PUFA (n-3 PUFA) supplementation on erythrocyte fatty acid content was examined in a cohort of 30 AAA patients as part of a 12 week randomized placebo-controlled clinical trial. Blood analyses identified associations between AAA and decreased linoleic acid (LA), and AAA and increased Δ6-desaturase activity and biosynthesis of arachidonic acid (AA) from LA. Omega-3 PUFA supplementation (1.5 g DHA + 0.3 g EPA/day) decreased red blood cell distribution width (14.8 ± 0.4% to 13.8 ± 0.2%; P = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%, P < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%; P < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17; P < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01; P < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

Macronutrient-specific effect of the MTNR1B genotype on lipid levels in response to 2 year weight-loss diets.

Compelling evidence indicates that lipid metabolism is in partial control of the circadian system. In this context, it has been reported that the melatonin receptor 1B (MTNR1B) genetic variant influences the dynamics of melatonin secretion, which is involved in the circadian system as a chronobiotic. The objective was to analyze whether the MTNR1B rs10830963 genetic variant was related to changes in lipid levels in response to dietary interventions with different macronutrient distribution in 722 overweight/obese subjects from the POUNDS Lost trial. We did not find a significant association between the MTNR1B genotype and changes in lipid metabolism. However, dietary fat intake significantly modified genetic effects on 2 year changes in total and LDL cholesterol (P interaction = 0.006 and 0.001, respectively). In the low-fat diet group, carriers of the sleep disruption G allele (minor allele) showed a greater reduction of total cholesterol (ß ± SE = -5.78 ± 2.88 mg/dl, P = 0.04) and LDL cholesterol (ß ± SE = -7.19 ± 2.37 mg/dl, P = 0.003). Conversely, in the high-fat diet group, subjects carrying the G allele evidenced a smaller decrease in total cholesterol (ß ± SE = 5.81 ± 2.65 mg/dl, P = 0.03) and LDL cholesterol (ß ± SE = 5.23 ± 2.21 mg/dl, P = 0.002). Subjects carrying the G allele of the circadian rhythm-related MTNR1B variant may present a bigger impact on total and LDL cholesterol when undertaking an energy-restricted low-fat diet.

Individual serum saturated fatty acids and markers of chronic subclinical inflammation: the Insulin Resistance Atherosclerosis Study.

Recent evidence has documented distinct effects of individual saturated FAs (SFAs) on cardiometabolic outcomes, with potential protective effects from odd- and very long-chain SFAs (VLSFAs). Cross-sectional and prospective associations of individual serum SFAs (12:0, 14:0, 15:0, 16:0, 18:0, 20:0, 22:0, and total SFA) with proinflammatory biomarkers and adiponectin were investigated in 555 adults from the IRAS. Principal component analysis (PCA) of proinflammatory markers yielded three clusters: principal component (PC) 1: fibrinogen, white cell count, C-reactive protein; PC 2: plasminogen activator inhibitor-1 (PAI-1), TNF-α, IL-18; PC 3: IL-6 and IL-8. Cross-sectional analyses on proinflammatory PCs and adiponectin, and prospective analyses on 5 year PAI-1 and fibrinogen concentrations were conducted with multiple regression. Total SFA and 16:0 were positively associated with PC 1 and PC 2, and negatively associated with adiponectin. The 14:0 was positively associated with PC 1 and negatively associated with adiponectin. In contrast, 15:0, 20:0, and 22:0 were negatively associated with PC 2, and 20:0 and 22:0 were positively associated with adiponectin. The 18:0 was negatively associated with PC 3. Prospectively, 15:0, 18:0, 20:0, and 22:0 were negatively associated with 5 year PAI-1 concentrations. The results demonstrate that individual SFAs have distinct roles in subclinical inflammation, highlighting the unique metabolic impacts of individual SFAs.

Dietary LA and sex effects on oxylipin profiles in rat kidney, liver, and serum differ from their effects on PUFAs.

A vast literature on fatty acids in mammals exists, but comparable compositional data on oxylipins is lacking. Weanling Sprague-Dawley rats were therefore provided control diets or diets with higher linoleic acid (LA) or with higher LA and α-linolenic acid (LA+ALA) for 6 weeks. Kidneys, livers, and serum were analyzed for oxylipins and fatty acids. The proportion of tissue oxylipins derived from LA was greater than the relative proportion of LA itself, whereas arachidonic acid (AA) oxylipins were overrepresented in serum. Higher dietary LA increased kidney LA and AA oxylipins, despite not altering LA or AA. In liver, both LA and AA and their oxylipins were higher, whereas in serum only LA oxylipins were higher with higher dietary LA. Higher LA resulted in a higher ratio of n-6/n-3 PUFA-derived oxylipins; adding ALA to the LA diet mitigated this and many, but not all, effects of the LA diet. Approximately 40% of oxylipins detected were influenced by sex and, unlike their PUFA precursors, most (>90%) of these were higher in males. These differences in dietary LA and sex on oxylipin and fatty acid profiles further our understanding of the effects of fatty acids and may have implications for dietary LA recommendations.

Imaging regiospecific lipid turnover in mouse brain with desorption electrospray ionization mass spectrometry.

Compartmentalization of metabolism into specific regions of the cell, tissue, and organ is critical to life for all organisms. Mass spectrometric imaging techniques have been valuable in identifying and quantifying concentrations of metabolites in specific locations of cells and tissues, but a true understanding of metabolism requires measurement of metabolite flux on a spatially resolved basis. Here, we utilize desorption ESI-MS (DESI-MS) to measure lipid turnover in the brains of mice. We show that anatomically distinct regions of the brain have distinct lipid turnover rates. These turnover measurements, in conjunction with relative concentration, will enable calculation of regiospecific synthesis rates for individual lipid species in vivo. Monitoring spatially dependent changes in metabolism has the potential to significantly facilitate research in many areas, such as brain development, cancer, and neurodegeneration.