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1.  CCAAT/Enhancer Binding Protein β in relation to ER Stress, Inflammation, and Metabolic Disturbances 
BioMed Research International  2015;2015:324815.
The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-β in these metabolic disturbances. C/EBP-β deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of β-oxidation genes in brown adipose tissue. Furthermore, C/EBP-β is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-β is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-β at molecular and physiological level in humans.
PMCID: PMC4324884
2.  Protective Role of Plant Sterol and Stanol Esters in Liver Inflammation: Insights from Mice and Humans 
PLoS ONE  2014;9(10):e110758.
The inflammatory component of non–alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.
PMCID: PMC4214692  PMID: 25356831
3.  Genetic Variation in FADS Genes and Plasma Cholesterol Levels in 2-Year-Old Infants: KOALA Birth Cohort Study 
PLoS ONE  2013;8(5):e61671.
Single nucleotide polymorphisms (SNPs) in genes involved in fatty acid metabolism (FADS1 FADS2 gene cluster) are associated with plasma lipid levels. We aimed to investigate whether these associations are already present early in life and compare the relative contribution of FADS SNPs vs traditional (non-genetic) factors as determinants of plasma lipid levels.
Information on infants’ plasma total cholesterol levels, genotypes of five FADS SNPs (rs174545, rs174546, rs174556, rs174561, and rs3834458), anthropometric data, maternal characteristics, and breastfeeding history was available for 521 2-year-old children from the KOALA Birth Cohort Study. For 295 of these 521 children, plasma HDLc and non-HDLc levels were also known. Multivariable linear regression analysis was used to study the associations of genetic and non-genetic determinants with cholesterol levels.
All FADS SNPs were significantly associated with total cholesterol levels. Heterozygous and homozygous for the minor allele children had about 4% and 8% lower total cholesterol levels than major allele homozygotes. In addition, homozygous for the minor allele children had about 7% lower HDLc levels. This difference reached significance for the SNPs rs174546 and rs3834458. The associations went in the same direction for non-HDLc, but statistical significance was not reached. The percentage of total variance of total cholesterol levels explained by FADS SNPs was relatively low (lower than 3%) but of the same order as that explained by gender and the non-genetic determinants together.
FADS SNPs are associated with plasma total cholesterol and HDLc levels in preschool children. This brings a new piece of evidence to explain how blood lipid levels may track from childhood to adulthood. Moreover, the finding that these SNPs explain a similar amount of variance in total cholesterol levels as the non-genetic determinants studied reveals the potential importance of investigating the effects of genetic variations in early life.
PMCID: PMC3648514  PMID: 23667444
4.  Beneficial Effects of Sitostanol on the Attenuated Immune Function in Asthma Patients: Results of an In Vitro Approach 
PLoS ONE  2012;7(10):e46895.
In vitro and animal studies have suggested that plant sterols and stanols increase cytokine production by T-helper-1 cells. This may be beneficial for patient groups characterized by a T-helper-2 dominant immune response, e.g. asthma patients. (1) to evaluate whether sitostanol induces a T-helper-1 shift in peripheral blood mononuclear cells (PBMCs) from asthma patients, and (2) to unravel the role of regulatory T-cells in this respect.
Methodology/Principal Findings
PBMCs from 10 asthma patients and 10 healthy subjects were isolated and incubated with 1.2 µM sitostanol, while stimulated with 5 µg/ml PHA. Similar amounts of cholesterol were used to determine whether effects were specific for plant stanols or for sterols in general. Changes in cytokine production were measured using antibody arrays and ELISAs. Changes in regulatory T-cell population size were measured by flow cytometry, using intracellular Foxp3 staining. Sitostanol increased production of IFNγ by 6.5% and IL-2 by 6.0% compared to cholesterol (p<0.01). No changes in IL-4 and IL-13 were found. Interestingly, this effect was only present in PBMCs from asthma patients. The number of Foxp3+ cells tended to increase and their activity, measured by IL-10 production, increased after sitostanol treatment in PBMCs from asthma patients compared to controls by 32.3% (p = 0.077) and 13.3% (p<0.05), respectively.
Altogether, the sitostanol-induced Thelper-1 shift in PBMCs from asthma patients and the stimulating effects of sitostanol on Treg cell numbers and activity indicate a possible novel approach for plant stanol ester enriched functional foods in the amelioration of asthmatic symptoms. Functional effects, however, require further evaluation.
PMCID: PMC3473039  PMID: 23091602
5.  Predicted Changes in Fatty Acid Intakes, Plasma Lipids, and Cardiovascular Disease Risk Following Replacement of trans Fatty Acid-Containing Soybean Oil with Application-Appropriate Alternatives 
Lipids  2012;47(10):951-962.
The varied functional requirements satisfied by trans fatty acid (TFA)—containing oils constrains the selection of alternative fats and oils for use as potential replacements in specific food applications. We aimed to model the effects of replacing TFA-containing partially hydrogenated soybean oil (PHSBO) with application-appropriate alternatives on population fatty acid intakes, plasma lipids, and cardiovascular disease (CVD) risk. Using the National Health and Nutrition Examination Survey 24-hour dietary recalls for 1999–2002, we selected 25 food categories, accounting for 86 % of soybean oil (SBO) and 79 % of TFA intake for replacement modeling. Before modeling, those in the middle quintile had a mean PHSBO TFA intake of 1.2 % of energy. PHSBO replacement in applications requiring thermal stability by either low-linolenic acid SBO or mid-oleic, low-linolenic acid SBO decreased TFA intake by 0.3 % of energy and predicted CVD risk by 0.7–0.8 %. PHSBO replacement in applications requiring functional properties with palm-based oils reduced TFA intake by 0.8 % of energy, increased palmitic acid intake by 1.0 % of energy, and reduced predicted CVD risk by 0.4 %, whereas replacement with fully hydrogenated interesterified SBO reduced TFA intake by 0.7 % of energy, increased stearic acid intake by 1.0 % of energy, and decreased predicted CVD risk by 1.2 %. PHSBO replacement in both thermal and functional applications reduced TFA intake by 1.0 % of energy and predicted CVD risk by 1.5 %. Based solely on changes in plasma lipids and lipoproteins, all PHSBO replacement models reduced estimated CVD risk, albeit less than previously reported using simpler replacement models.
PMCID: PMC3449058  PMID: 22903557
trans fatty acid; Partially hydrogenated soybean oil (PHSBO); Cardiovascular disease; Linolenic acid
6.  Trans Fatty Acid Intakes and Food Sources in the U.S. Population: NHANES 1999–2002 
Lipids  2012;47(10):931-940.
Because of efforts to decrease trans fatty acids (TFA) in the food supply, intake should be assessed in the population to establish a baseline TFA intake. The 1999–2002 National Health and Nutrition Examination Survey (NHANES) was used to identify a benchmark for TFA intake. TFA was estimated by mean, median, and quintile of intake, TFA intake data were weighted using the NHANES 4-year sample weights. The main outcome measures included TFA intake in grams per day and percentage of energy in the top 25 food sources of TFA. Data are reported for 16,669 individuals ≥3 years of age. Median TFA intake was 2.3 % of calories (5 g/day) with 0.9–4.5 % of energy (1.5–13.1 g/day) over different quintiles of intake. Mean TFA intake was 2.5 % of energy (6.1 g/day). The range of TFA intake in the fifth quintile was very large, i.e., 3.5–12.5 % of energy or 8.8–92.4 g/day. Increasing quintiles of TFA intake were associated with increases in total fat (26.7–37.6 % of energy), saturated fat (7.6–10.5 % of energy), and calories (for those >20 years of age: 2,416–2,583 for men and 1,679–1,886 for women). Major food sources of dietary TFA were cakes, cookies, pies, and pastries. Based on current dietary guidance to consume as little industrial TFA as possible, much progress is needed to attain this goal, including food industry efforts to remove TFA from the food supply and educating the public about making healthy food choices.
PMCID: PMC3449059  PMID: 22903556
Trans fatty acid intake; Industrial trans fatty acid intake; Fatty acid intake; Quintiles of trans fatty acid intake; Food sources of trans fatty acids; NHANES 1999–2002
7.  Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation 
Cellular and Molecular Life Sciences  2010;68(7):1215-1225.
Palmitate activates the NF-κB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-κB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-κB activation are causally related. Inhibiting DGAT or CPT-1 by using, respectively, amidepsine or etomoxir increased DAG accumulation and sensitized myotubes to palmitate-induced insulin resistance. While co-incubation of palmitate with etomoxir increased NF-κB transactivation, co-incubation with amidepsine did not, indicating that DAG accumulation is associated with insulin resistance but not with NF-κB activation. Furthermore, pharmacological or genetic inhibition of the NF-κB pathway could not prevent palmitate-induced insulin resistance. In conclusion, we have demonstrated that activation of the NF-κB pathway is not required for palmitate-induced insulin resistance in skeletal muscle cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s00018-010-0515-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3056136  PMID: 20820848
Skeletal muscle; Insulin resistance; Palmitate; Nuclear factor-kappa B; Glucose uptake
8.  Fatty Acid- and Cholesterol Transporter Protein Expression along the Human Intestinal Tract 
PLoS ONE  2010;5(4):e10380.
Protein distribution profiles along the human intestinal tract of transporters involved in the absorption of cholesterol and long-chain fatty acids (LCFA) have been scarcely evaluated.
Methodology/Principal Findings
In post-mortem samples from 11 subjects, intestinal transporter distribution profiles were determined via Western Blot. Differences in transporter protein levels were statistically tested using ANOVA and Tukey's Post Hoc comparisons. Levels in all segments were expressed relative to those in duodenum. Except for ABCG5 and FATP4, levels (mean±SEM) were the highest in the ileum. For ABCA1, ileal levels (1.80±0.26) differed significantly from those in duodenum (P = 0.049) and proximal colon (0.92±0.14; P = 0.029). ABCG8 levels in ileum (1.91±0.30) differed from those in duodenum (P = 0.041) and distal colon (0.84±0.22; P = 0.010) and jejunum (1.64±0.26) tended to be higher than distal colon (0.84±0.22; P = 0.087). Ileal NPC1L1 levels (2.56±0.51) differed from duodenum levels (P = 0.019) and from distal colon (1.09±0.22; P = 0.030). There was also a trend (P = 0.098) for higher jejunal (2.23±0.37) than duodenal NPC1L1 levels. The levels of ABCG5 did not correlate with those of ABCG8. FAT/CD36 levels in ileum (2.03±0.42) differed from those in duodenum (P = 0.017), and proximal and distal colon (0.89±0.13 and 0.97±0.15 respectively; P = 0.011 and P = 0.014). FABPpm levels in ileum (1.04±0.13) differed from proximal (0.64±0.07; P = 0.026) and distal colon (0.66±0.09; P = 0.037).
The distribution profiles showed a bell-shape pattern along the GI-tract with the highest levels in ileum for ABCA1, ABCG8, NPC1L1, FATCD36 and FABPm, suggesting a prominent role for ileum in transporter-mediated uptake of cholesterol and LCFAs.
PMCID: PMC2861623  PMID: 20454462
9.  Plant Stanol Esters Lower Serum Triacylglycerol Concentrations via a Reduced Hepatic VLDL-1 Production 
Lipids  2009;44(12):1149-1153.
Plant stanol esters not only lower low density lipoprotein cholesterol but also have previously been shown to lower serum triacylglycerol (TAG) concentrations, especially in subjects with elevated TAG concentrations. To find a possible explanation, we explored changes in serum lipoprotein profiles, as measured with nuclear magnetic resonance. For this, serum samples from two parallel-designed controlled studies were evaluated before and 8 weeks after the consumption of plant stanol esters. In the first study, dyslipidemic metabolic syndrome subjects participated and in the second study normolipidemic subjects. In metabolic syndrome subjects, plant stanol esters lowered concentrations of large (>60 nm) and medium (35–60 nm) VLDL particles as compared to controls. In normolipidemic subjects, the serum concentration of large VLDL-1 particles was also lowered, although less pronounced. Based on these findings, we hypothesize that the effect of plant stanol esters on serum TAG concentrations origins from a lowered hepatic production of large TAG-rich VLDL-1 particles.
PMCID: PMC2779439  PMID: 19856194
Plant stanol esters; Diet; Triacylglycerol; Lipoproteins
10.  Anti-inflammatory effect of rosiglitazone is not reflected in expression of NFκB-related genes in peripheral blood mononuclear cells of patients with type 2 diabetes mellitus 
Rosiglitazone not only improves insulin-sensitivity, but also exerts anti-inflammatory effects. We have now examined in type 2 diabetic patients if these effects are reflected by changes in mRNA expression in peripheral blood mononuclear cells (PBMCs) to see if these cells can be used to study these anti-inflammatory effects at the molecular level in vivo.
Eleven obese type 2 diabetic patients received rosiglitazone (2 × 4 mg/d) for 8 weeks. Fasting blood samples were obtained before and after treatment. Ten obese control subjects served as reference group. The expression of NFκB-related genes and PPARγ target genes in PBMCs, plasma TNFα, IL6, MCP1 and hsCRP concentrations were measured. In addition, blood samples were obtained after a hyperinsulinemic-euglycemic clamp.
Rosiglitazone reduced plasma MCP1 and hsCRP concentrations in diabetic patients (-9.5 ± 5.3 pg/mL, p = 0.043 and -1.1 ± 0.3 mg/L p = 0.003), respectively). For hsCRP, the concentration became comparable with the non-diabetic reference group. However, of the 84 NFκB-related genes that were measured in PBMCs from type 2 diabetic subjects, only RELA, SLC20A1, INFγ and IL1R1 changed significantly (p < 0.05). In addition, PPARγ and its target genes (CD36 and LPL) did not change. During the clamp, insulin reduced plasma MCP1 concentration in the diabetic and reference groups (-9.1 ± 1.8%, p = 0.001 and -11.1 ± 4.1%, p = 0.023, respectively) and increased IL6 concentration in the reference group only (23.5 ± 9.0%, p = 0.028).
In type 2 diabetic patients, the anti-inflammatory effect of rosiglitazone is not reflected by changes in NFκB and PPARγ target genes in PBMCs in vivo. Furthermore, our results do not support that high insulin concentrations contribute to the pro-inflammatory profile in type 2 diabetic patients.
PMCID: PMC2653037  PMID: 19243600
11.  Arachidonic Acid but not Eicosapentaenoic Acid (EPA) and Oleic Acid Activates NF-κB and Elevates ICAM-1 Expression in Caco-2 Cells  
Lipids  2007;42(8):687-698.
In patients with inflammatory bowel disease (IBD), intestinal activation of the transcription factor NF-κB as well as intercellular adhesion molecule (ICAM)-1 expression, which is involved in recruiting leukocytes to the side of inflammation is increased. Moreover, colonic arachidonic acid (ARA) proportions are increased and oleic acid (OA) proportions are decreased. Fish oils are protective in IBD patients however, a side-by-side comparison between effects of fish oils, ARA and OA has not been made. We therefore, compared effects of eicosapentaenoic acid (EPA) versus ARA and OA on ICAM-1 expression in Caco-2 enterocytes. To validate our model we showed that dexamethasone, sulfasalazine and PPARα (GW7647) or PPARγ (troglitazone) agonists significantly lowered ICAM-1 expression. ICAM-1 expression of non-stimulated and cytokine stimulated Caco-2 cells cultured for 22 days with ARA was significant higher as compared to EPA and OA. Furthermore, ARA increased NF-κB activation in a reporter cell-line as compared to EPA. Antibody array analysis of multiple inflammatory proteins particularly showed an increased monocyte chemotactic protein (MCP)-1 and angiogenin production and a decreased interleukin (IL)-6 and IL-10 production by ARA as compared to EPA. Our results showed that ARA but not EPA and OA activates NF-κB and elevates ICAM-1 expression in Caco-2 enterocytes. It suggests that replacement of ARA by EPA or OA in the colon mucosa might have beneficial effects for IBD patients. Finally, we suggest that the pro-inflammatory effects of ARA versus EPA and OA are not related to PPARγ activation and/or eicosanoid formation.
PMCID: PMC2039812  PMID: 17610002
Intestinal inflammation; Caco-2 cells; Prostaglandins; Peroxisome proliferator-activated receptor (PPAR)
12.  The PPARγ Agonist Rosiglitazone Impairs Colonic Inflammation in Mice with Experimental Colitis 
Journal of Clinical Immunology  2007;27(3):275-283.
Various animal models showed that peroxisome proliferator-activated receptor (PPAR)γ agonists, when given as a gavage shortly preceding colitis induction, protect against inflammatory bowel disease (IBD). We have examined the effects of 16 days rosiglitazone treatment via the diet prior to dextran sodium sulphate (DSS)-induced colitis in mice. After 7 days DSS in the drinking water, rosiglitazone-fed mice had lost significantly more weight than control mice. Rosiglitazone-treated mice had more diarrhea, weight of colon and spleen were increased, and length of colon was decreased. Histology showed that rosiglitazone-treated mice had more severe colitis, mainly caused by more ulceration, crypt loss, and edema. Immunofluorescence showed a loss of tight junction structure Zonula Occludens protein 1 (ZO-1) in colons of rosiglitazone-treated mice as compared to control mice. Also, serum amyloid P component (SAP) concentrations in plasma were increased. However, concentrations of tumor necrosis factor (TNF)-α and interferon (IFN)-γ in colon homogenates, and TNF-α in spleen homogenates were significantly decreased, whereas interleukin (IL)-10 in spleen homogenates was increased. Other cytokines (IL-2, IL-4, IL-6, IL-12p70 and monocyte chemotactic protein (MCP)-1) and myeloperoxidase (MPO) concentrations showed no differences. In conclusion, 16 days pretreatment with rosiglitazone impaired DSS-induced colitis in mice.
PMCID: PMC1915631  PMID: 17510806
DSS-induced colitis; rosiglitazone; peroxisome proliferator-activated receptor; PPAR

Results 1-12 (12)