Lars Hellgren

Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine.

Endocannabinoids and N-acylethanolamines are lipid mediators regulating a wide range of biological functions including food intake. We investigated short-term effects of feeding rats five different dietary fats (palm oil (PO), olive oil (OA), safflower oil (LA), fish oil (FO) and arachidonic acid (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum without changing levels of anandamide, suggesting that dietary fat may have an orexigenic effect. The AA-diet increased anandamide and 2-arachidonoylglycerol in jejunum without effect on liver. The FO-diet decreased liver levels of all N-acylethanolamines (except eicosapentaenoylethanolamide and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high in monounsaturated fat, diet high in saturated fat, or diet high in polyunsaturated fat) can affect tissue levels of endocannabinoids and N-acylethanolamines.

Human gut microbes impact host serum metabolome and insulin sensitivity

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema

To cite this article: Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK, Hellgren LI, Jemec GBE, Agner T, Weidinger S. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010; 65: 911–918.

Lipids and skin barrier function : a clinical perspective

The stratum corneum (SC) protects us from dehydration and external dangers. Much is known about the morphology of the SC and penetration of drugs through it, but the data are mainly derived from in vitro and animal experiments. In contrast, only a few studies have the human SC lipids as their focus and in particular, the role of barrier function in the pathogenesis of skin disease and its subsequent treatment protocols. The 3 major lipids in the SC of importance are ceramides, free fatty acids, and cholesterol. Human studies comparing levels of the major SC lipids in patients with atopic dermatitis and healthy controls have suggested a possible role for ceramide 1 and to some extent ceramide 3 in the pathogenesis of the disease. Therapies used in diseases involving barrier disruption have been sparely investigated from a lipid perspective. It has been suggested that ultraviolet light as a treatment increases the amount of all 3 major SC lipids, while topical glucocorticoids may lead to a decrease. Such effects may influence the clinical outcome of treatment in diseases with impaired barrier function. We have, therefore, conducted a review of the literature on SC lipids from a clinical perspective. It may be concluded that the number of human studies is very limited, and in the perspective of how important diseases of impaired barrier function are in dermatology, further research is needed.

FADS genotype and diet are important determinants of DHA status: a cross-sectional study in Danish infants

BACKGROUND Infant docosahexaenoic acid (DHA) status is supported by the DHA content of breast milk and thus can decrease once complementary feeding begins. Furthermore, it is unclear to what extent endogenous DHA synthesis contributes to status. OBJECTIVE We investigated several determinants, including FADS genotypes on DHA status at 9 mo and 3 y. DESIGN This was a cross-sectional study with Danish infants from 2 prospective studies [Essentielle Fedtsyrer i OvergangskosteN (EFiON) and the Småbørns Kost Og Trivsel (SKOT) cohort] in which we measured red blood cell (RBC) DHA status at 9 mo (n = 409) and 3 y (n = 176) and genotyped 4 FADS tag single nucleotide polymorphisms (SNPs): rs3834458, rs1535, rs174575, and rs174448 (n = 401). Information about breastfeeding was obtained by using questionnaires, and fish intake was assessed by using 7-d precoded food diaries. RESULTS FADS genotype, breastfeeding, and fish intake explained 25% of the variation in infant RBC DHA status [mean ± SD: 6.6 ± 1.9% of fatty acids (FA%)]. Breastfeeding explained most of the variation (∼20%), and still being breastfed at 9 mo was associated with a 0.7 FA% higher DHA compared with no longer being breastfed (P < 0.001). The FADS SNPs rs1535 and rs3834458 were highly correlated (r = 0.98). Homozygous carriers of the minor allele of rs1535 had a DHA increase of 1.8 FA% (P = 0.001) relative to those with the wild-type allele, whereas minor allele carriers of rs174448 and rs174575 had a decrease of 1.1 FA% (P = 0.005) and 2.0 FA% (P = 0.001), respectively. Each 10-g increment in fish intake was associated with an increased DHA status of 0.3 FA%. At 3 y, fish intake was the only significant determinant of DHA status (0.2 FA%/10 g). CONCLUSION Breastfeeding, FADS genotype, and fish intake are important determinants of DHA status in late infancy. The EFiON study was registered at clinicaltrials.gov as NCT 00631046.

Phytanic acid—an overlooked bioactive fatty acid in dairy fat?

Phytanic acid is a multibranched fatty acid with reported retinoid X receptor (RXR) and peroxisome proliferator‐activated receptor‐α (PPAR‐α) agonist activity, which have been suggested to have preventive effects on metabolic dysfunctions. Serum level in man is strongly correlated to the intake of red meat and dairy products and the concentration in these products is strongly correlated to the chlorophyll content in the feed of the cattle. Available data suggest that phytanic acid is a natural agonist for RXR at physiological concentrations, while it is more likely that it is the metabolite pristanic acid, rather than phytanic acid itself, that acts as PPAR‐α agonist. Animal studies show increased expression of genes involved in fatty acid oxidation, after intake of phytol, the metabolic precursor of phytanic acid, but it is at present not possible to deduce whether phytanic acid is useful in the prevention of ectopic lipid deposition. Phytanic acid is an efficient inducer of the expression of uncoupler protein 1 (UCP1). UCP1 is expressed in human skeletal muscles, were it might be important for the total energy balance. Therefore, phytanic acid may be able to stimulate energy dissipation in skeletal muscles. Phytanic acid levels in serum are associated with an increased risk of developing prostate cancer, but the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk. However, certain individuals, with specific single‐nucleotide polymorphisms in the gene for the enzyme alpha‐methylacyl‐CoA racemase, might be susceptible to raised phytanic acid levels.

Effect of gender on lipid-induced insulin resistance in obese subjects

OBJECTIVE In obese subjects, chronically elevated plasma concentrations of non-esterified fatty acids (NEFAs) exert a marked risk to contract insulin resistance and subsequently type 2 diabetes. When NEFA is acutely increased due to i.v. infusion of lipid, glucose disposal during a hyperinsulinemic-euglycemic clamp is reduced. This effect has been explained by a NEFA-induced decrease in skeletal muscle insulin sensitivity caused by accumulation of the lipid intermediates such as ceramide and diacylglycerol in the myocytes. However, neither the lipid-induced reduction of glucose disposal nor the intramyocellular lipid deposition has been compared directly in obese females and males. DESIGN We studied eight obese females and eight obese males (body mass index (BMI): 32.6+/-1.4 and 32.8+/-0.8 respectively, non significant (NS)) matched for cardiorespiratory fitness relative to lean body mass (43.7+/-1.6 and 47.6+/-1.3 ml/kg min respectively, NS). METHODS Each subject underwent two hyperinsulinemic-euglycemic clamps with infusion of lipid or saline respectively. Furthermore, the subjects exercised during the last half an hour of each clamp. RESULTS The lipid-induced reduction in glucose disposal during the clamp was similar in females and males (46+/-10 and 60+/-4% respectively, NS). However, whole-body insulin sensitivity as well as non-oxidative glucose disposal was higher in obese females compared with obese males both during lipid and saline infusion (P<0.001 and P=0.01 respectively). Muscle ceramide, triacylglycerol (TAG), diacylglycerol (DAG), and glycogen content were similar between sexes and remained unchanged during the clamp and when exercise was superimposed. CONCLUSIONS The lipid-induced inhibition of glucose disposal is similar in obese females and males. However, obese females are more insulin sensitive compared with obese males (both during saline and lipid infusion), which is not due to differences in the concentration of the muscle lipid intermediates such as ceramide and DAG.

Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women

Consumption of industrially produced trans fatty acids (IP-TFA) has been positively associated with systemic markers of low-grade inflammation and endothelial dysfunction in cross-sectional studies, but results from intervention studies are inconclusive. Therefore, we conducted a 16 week double-blind parallel intervention study with the objective to examine the effect of IP-TFA intake on biomarkers of inflammation, oxidative stress, and endothelial dysfunction. Fifty-two healthy overweight postmenopausal women (49 completers) were randomly assigned to receive either partially hydrogenated soybean oil (15.7 g/day IP-TFA) or control oil without IP-TFA. After 16 weeks, IP-TFA intake increased baseline-adjusted serum tumor necrosis factor (TNF) α by 12% [95% confidence interval (CI): 5–20; P = 0.002] more in the IP-TFA group compared with controls. Plasma soluble TNF receptors 1 and 2 were also increased by IP-TFA [155 pg/ml (CI: 63–247); P < 0.001 and 480 pg/ml (CI: 72–887); P = 0.02, respectively]. Serum C-reactive protein, interleukin (IL) 6 and adiponectin and subcutaneous abdominal adipose tissue mRNA expression of IL6, IL8, TNFα, and adiponectin as well as ceramide content were not affected by IP-TFA, nor was urinary 8-iso-prostaglandin-F2α. In conclusion, this dietary trial indicates that the mechanisms linking dietary IP-TFA to cardiovascular disease may involve activation of the TNFα system.

Effects of Fish Oil Supplementation on Markers of the Metabolic Syndrome

OBJECTIVE To investigate whether fish oil affects cardiovascular risk factors during the adolescent growth spurt. STUDY DESIGN A total of 78 boys age 13-15 years with a mean body fat percentage of 30%+/-9% were randomly assigned to consume fish oil (providing 1.5 g of n-3 long-chain polyunsaturated fatty acid/day) or vegetable oil (control) for 16 weeks. The oils were included in bread. RESULTS After the intervention, the red blood cell (RBC) content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were 1.2%+/-0.5% and 6.7%+/-1.6%, respectively, in the those receiving fish oil (FO group), compared with 0.6%+/-0.3% and 4.1%+/-0.9% in the control group. Systolic blood pressure (SBP) was 3.8+/-1.4 mm Hg lower (P<.006) and diastolic blood pressure (DBP) was 2.6+/-1.1 mm Hg lower (P<.01) in the FO group compared with the control group. Plasma triacylglycerol (TAG) concentration and insulin sensitivity were unaffected by either of the treatments. Plasma high-density lipoprotein (HDL) and non-HDL cholesterol were increased by 5% and 7%, respectively, in the FO group, and by 2% and 0% in the control group (P<.01-.02). The changes in RBC EPA content were inversely correlated with the changes in SBP and DBP and directly correlated with the increases in HDL cholesterol and non-HDL cholesterol concentrations. No association was seen between RBC EPA and plasma TAG concentration or insulin sensitivity. CONCLUSION Fish oil improves BP in normotensive and normolipidemic slightly overweight adolescent boys.

Lipid asymmetry in plant plasma membranes: phosphate deficiency-induced phospholipid replacement is restricted to the cytosolic leaflet

As in other eukaryotes, plant plasma membranes contain sphingolipids, phospholipids, and free sterols. In addition, plant plasma membranes also contain sterol derivatives and usually <5 mol% of a galactolipid, digalactosyldiacylglycerol (DGDG). We earlier reported that compared to fully fertilized oats (Avena sativa), oats cultivated without phosphate replaced up to 70 mol% of the root plasma membrane phospholipids with DGDG. Here, we investigated the implications of a high DGDG content on membrane properties. The phospholipid‐to‐DGDG replacement almost exclusively occurred in the cytosolic leaflet, where DGDG constituted up to one‐third of the lipids. In the apoplastic (exoplasmic) leaflet, as well as in rafts, phospholipids were not replaced by DGDG, but by acylated sterol glycosides. Liposome studies revealed that the chain ordering in free sterol/phospholipid mixtures clearly decreased when > 5 mol% DGDG was included. As both the apoplastic plasma membrane leaflet (probably the major water permeability barrier) and rafts both contain only trace amounts of DGDG, we conclude that this lipid class is not compatible with membrane functions requiring a high degree of lipid order. By not replacing phospholipids site specifically with DGDG, negative functional effects of this lipid in the plasma membrane are avoided.—Tjellstrom, H., Hellgren, L. I., Wieslander, A., Sandelius, A. S. Lipid asymmetry in plant plasma membranes: phosphate deficiency‐induced phospholipid replacement is restricted to the cytosolic leaflet. FASEB J. 24, 1128–1138 (2010). www.fasebj.org