| 1. |
- Fridén, Michael, et al.
(författare)
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Effects of a low-carbohydrate high polyunsaturated fat diet or a healthy Nordic diet versus usual care on liver fat content and cardiometabolic risk factors in people with type 2 diabetes and prediabetes: a randomized controlled trial (NAFLDiet)
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Previous trials have shown that plant-derived polyunsaturated fatty acids (PUFA) in place of saturated fat reduces liver fat, a prerequisite for non-alcoholic fatty liver disease (NAFLD). The effect on liver fat from a novel “anti-lipogenic diet” replacing carbohydrates with PUFA or a healthy Nordic diet (HND) higher in whole-grains but lower in saturated fat has not yet been examined. Objectives: To investigate the effects on changes in liver fat (primary outcome) and other cardiometabolic risk factors after 12 months of follow-up in individuals with prediabetes or T2D from three different diet comparisons: a low carbohydrate high PUFA (LCPUFA) diet versus a HND, a LCPUFA diet versus usual care (UC) and a HND versus UC. Methods: A three-arm parallel ad libitum randomized trial was conducted. Adult men and women (n=148) were randomized to one of the three diet groups. Participants in all groups received key food items on a monthly/bimonthly basis. Liver fat and cardiometabolic risk factors were assessed at baseline and after 12 months. Dietary adherence was assessed using weighed food diaries and objective biomarkers. General linear models were employed to estimate the intention-to-treat (ITT) effect. Results: Dietary adherence was high for all diet groups. Liver fat was reduced to a similar extent in the LCPUFA and the HND group compared to UC (-1.46% (95% CI: -2.42, -0.51)) and -1.76 % (95% CI: -2.96, -0.57), respectively. No difference in liver fat between LCPUFA and HND was observed. Body weight and HbA1c decreased more in the HND compared to the other diet groups whereas no differences were observed between LCPUFA and UC. Similar reductions in LDL-cholesterol were observed for the HND and the LCPUFA group compared to UC, but only the HND reduced triglycerides and C-reactive protein (CRP) compared with UC. No differences were observed for any other secondary outcomes.Conclusions: A LCPUFA diet and a HND both reduced liver fat as compared with UC. Given the sustained weight loss after the HND compared to the other groups, together with improvements in other cardiometabolic markers, the HND in particular seems to be useful for the treatment of T2D and NAFLD.
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| 2. |
- Fridén, Michael, et al.
(författare)
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Hepatic Unsaturated Fatty Acids Are Linked to Lower Degree of Fibrosis in Non-alcoholic Fatty Liver Disease
- 2022
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited. Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0–1) or significant fibrosis (F2–4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions. Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis. Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.
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| 3. |
- Rosqvist, Fredrik, 1985-, et al.
(författare)
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Circulating fatty acids from high-throughput metabolomics platforms as potential biomarkers of dietary fatty acids
- 2022
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 41:12, s. 2637-2643
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Tidskriftsartikel (refereegranskat)abstract
- Background Some fatty acids, i.e. n-3 and n-6 polyunsaturated fatty acids (PUFA), from metabolomics platforms based on nuclear magnetic resonance imaging (NMR) or liquid chromatography mass-spectrometry (LC-MS) are suggested to reflect dietary exposure. NMR and LC-MS are both relatively fast and cheap, however few studies have investigated their validity. Linoleic acid (LA) and docosahexaenoic acid (DHA), measured using gas chromatography (GC), are established biomarkers of dietary n-6 and n-3 PUFA intake, respectively.Objective To examine if circulating fatty acids derived from two commonly applied metabolomics platforms (using NMR and LC-MS) provide similar information compared to GC in two pooled population-based cohorts, one patient cohort, and in a randomized controlled trial (RCT).Methods Spearman rank correlations were conducted between LA and DHA in cholesteryl esters (CE) from GC and whole serum/plasma LA and DHA from the metabolomics platforms in a pooled population-based cohort of men and women (n ˜ 1100) (primary analysis). Secondary correlation analyses included fatty acid classes such as n-3 PUFA, n-6 PUFA, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and total PUFA. Additionally, correlations were investigated for LA, DHA and the five fatty acid classes in phospholipids (PL), triacylglycerols (TAG) and non-esterified fatty acids (NEFA) in a RCT of n = 60 as well as in a population with biopsy-verified non-alcoholic fatty liver disease (NAFLD) (n = 59). Misclassification was examined using cross-tabulation and visualized using alluvial plots.Results Moderate to strong correlations (r = 0.51–0.81) were observed for LA and DHA in multiple lipid fractions in all cohorts using the NMR platform. For the pooled cohort, LA (r = 0.67, P < 0.0001) and DHA (r = 0.68, P < 0.0001) assessed in CE were strongly correlated with LA and DHA derived using NMR. Nearly half (49%) were correctly classified into their respective quartiles. Using LC-MS, only DHA (r = 0.44, P < 0.0001) demonstrated moderate correlations with DHA from GC.Conclusions Unless fatty acid data from GC analysis is available or feasible, NMR-based technology might be a better option than a LC-MS-based platform, at least for certain PUFA. This should be taken into account in future studies aiming to use circulating fatty acids as dietary biomarkers for the investigation of diet-disease relationships.
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| 4. |
- Rosqvist, Fredrik, 1985-, et al.
(författare)
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Fatty acids in multiple circulating lipid fractions reflects the composition of liver triglycerides in humans
- 2022
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 1532-1983 .- 0261-5614. ; 41:4, s. 805-809
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Fatty acids (e.g. 16:1n-7) and desaturase indices (e.g. stearoyl-CoA desaturase, SCD) in plasma cholesteryl esters (CE) and phospholipids (PL) are used as biomarkers of dietary fat quality and lipid metabolism and are associated with disease outcomes. Endogenously produced circulating fatty acids are believed to reflect composition of the liver, yet little data exist to support such relationship. We investigated associations between circulating fatty acids and fatty acids within the liver. Methods: Liver biopsies and blood were collected from n = 60 patients with non-alcoholic fatty liver disease. Fatty acids in CE, PL and triglycerides (TG) in plasma and liver were analyzed using gas chromatography. Associations were assessed using Spearman rank correlations. Results: Overall, fatty acids and desaturase indices in plasma PL and TG showed moderate–strong correlations with fatty acids and desaturase indices in corresponding lipid fractions in liver. For plasma CE, 16:1n-7 and SCD were correlated with 16:1n-7 and SCD in liver CE. Noteworthy, fatty acids in plasma CE and PL also showed moderate–strong correlations with fatty acids in liver TG (e.g. r = 0.82–0.87 for 16:1n-7 and r = 0.77 for SCD). Conclusion: We demonstrate that fatty acids in circulating lipid fractions, including CE, TG and PL, reflects the composition of liver TG in humans, suggesting that circulating fatty acids might be useful biomarkers for the fatty acid composition of the liver. As liver tissue is rarely available in cohort studies, our findings could enhance our understanding of plasma fatty acids as markers of hepatic lipid metabolism and their links to metabolic diseases.
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| 5. |
- Bajahzer, Mohammed F., et al.
(författare)
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Contrasting Carbohydrate Quantity and Quality and the Effects on Plasma Saturated and Monounsaturated Fatty Acids in Healthy Adults : A Randomized Controlled Trial
- 2023
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Ingår i: Journal of Nutrition. - : Elsevier. - 0022-3166 .- 1541-6100. ; 153:3, s. 683-690
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unclear whether moderate differences in dietary carbohydrate quantity and quality influence plasma FAs in the lipogenic pathway in healthy adults.Objectives: We investigated the effects of different carbohydrate quantities and quality on plasma palmitate concentrations (primary outcome) and other saturated and MUFAs in the lipogenic pathway.Methods: Twenty healthy participants were randomly assigned, and 18 (50% women; age: 22-72 y; BMI: 18.2-32.7 kg/m2 and BMI was measured in kg/m2) started the cross-over intervention. During each 3-wk period (separated by a 1-wk washout period), 3 diets were consumed (all foods provided) in random order: low-carbohydrate (LC) (38% energy (E) carbohydrates, 25-35 g fiber/d, 0% E added sugars); high-carbohydrate/high-fiber (HCF) (53% E carbohydrates, 25-35 g fiber/d, 0% E added sugars); and high-carbohydrate/high-sugar (HCS) (53% E carbohydrates, 19-21 g fiber/d, 15% E added sugars). Individual FAs were measured proportionally to total FAs by GC in plasma cholesteryl esters, phospholipids, and TGs. False discovery rate-adjusted repeated measures ANOVA [ANOVA-false discovery rate (FDR)] was used to compare outcomes.Results: The self-reported intakes of carbohydrates and added-and free sugars were; 30.6% E and 7.4% E in LC, 41.4% E and 6.9% E in HCF, and 45.7% E and 10.3% in HCS. Plasma palmitate did not differ between the diet periods (ANOVA FDR P > 0.43, n = 18). After HCS, myristate concentrations in cholesterol esters and phospholipids were >= 19% higher than LC and >= 22% higher than HCF (P = 0.005). After LC, palmitoleate in TG was 6% lower compared with HCF and 7% compared with HCS (P = 0.041). Body weight differed (<= 0.75 kg) between diets before FDR correction.Conclusions: Different carbohydrate quantity and quality do not influence plasma palmitate concentrations after 3 wk in healthy Swedish adults, whereas myristate increased after the moderately higher intake of carbohydrate/high-sugar, but not carbohydrate/high-fiber. Whether plasma myristate is more responsive than palmitate to differences in carbohydrate intake requires further study, especially considering that participants deviated from the planned dietary targets.
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| 6. |
- Bajahzer, Mohammed Fahad, et al.
(författare)
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Effects of sugar-sweetened soda on plasma saturated and monounsaturated fatty acids in individuals with obesity : A randomized study.
- 2022
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Ingår i: Frontiers in nutrition. - : Frontiers Media SA. - 2296-861X. ; 9, s. 936828-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High carbohydrate, i.e., sugars, intake potentially drives the liver into a lipogenic state leading to elevated plasma fatty acids. Excessive intake of saturated fat and sugar-sweetened soda induces liver fat accumulation, but studying the effect of high intake from sugar-sweetened soda on the de novo lipogenesis (DNL) fatty acids in long-term randomized trials is lacking.OBJECTIVE: To study the effect of consuming 1 L/day of sugar-sweetened soda, semi-skimmed milk (milk), aspartame-sweetened soda or water over 24 weeks on DNL-derived fatty acids (i.e., palmitate (primary outcome) and other saturated and monounsaturated fatty acids), and markers of stearoyl-CoA desaturase activity (SCD1) in plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG).DESIGN AND METHODS: A randomized parallel study was conducted simultaneously at Aarhus University Hospital and Copenhagen University, Denmark, including (n = 41) individuals aged 20-50 years, with BMI of 26-40 kg/m2, and without diabetes. The groups consisted of 9 individuals in the sugar-sweetened soda, 10 in the milk, 11 in the aspartame-sweetened soda, and 11 in the water. The change at 24 weeks was assessed and compared across the groups using ANCOVA and mixed-effects models. Correlations of fatty acid changes with liver fat accumulation (magnetic resonance imaging) were explored.RESULTS: After 24 weeks, the groups differed in palmitate proportions in PL, oleate in CE and PL, and palmitoleate and SCD1 in all fractions (p < 0.05). Compared with water, the relative proportion of palmitate in PL increased by approximately 1% during both sugar-sweetened soda (p = 0.011) and milk (p = 0.006), whereas oleate and palmitoleate increased only during sugar-sweetened soda (CE 2.77%, p < 0.001; PL 1.51%, p = 0.002 and CE 1.46%, PL 0.24%, TG 1.31%, all p < 0.001, respectively). Liver fat accumulation correlated consistently with changes in palmitoleate, whereas correlations with palmitate and oleate were inconsistent across lipid fractions.CONCLUSIONS: Although both sugar-sweetened soda and milk increased palmitate in PL, only excess intake of sugar-sweetened soda increased palmitoleate in all lipid fractions and correlated with liver fat. In contrast, isocaloric milk intake did not increase plasma monounsaturated fatty acids.CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/ct2/show/NCT00777647], identifier [NCT00777647].
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| 7. |
- Beretta, Chiara, et al.
(författare)
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Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background. Astrocytes are critical for maintaining brain homeostasis, but are also highly involved in neuroinflammation. In the Alzheimer disease (AD) brain, reactive, inflammatory astrocytes are situated closely around amyloid β (Aβ) plaques. We have previously shown that reactive astrocytes ingest large quantities of soluble Aβ aggregates, but are unable to degrade the material, which leads to intracellular Aβ accumulation and severe cellular stress. A common response to cellular stress is the formation of lipid droplets (LDs). Novel data indicate that LDs play an important role in inflammatory processes. However, the involvement of LDs in AD inflammation and progression remains unclear.Methods. The aim of this study was to investigate how astrocytic Aβ pathology affects lipid metabolism and antigen presentation. For this purpose, human induced pluripotent stem cell (iPSC) derived astrocytes were exposed to soluble Aβ42 aggregates and analyzed over time, using a battery of experimental approaches.Results. Our results show that Aβ exposure induces LD accumulation in astrocytes, although the overall lipid composition remains unchanged. Moreover, astrocytes transfer LDs to neighboring cells via tunneling nanotubes (TNTs) and extracellular vesicle (EVs). Interestingly, we found that the antigen presenting protein major histocompatibility complex II (MHCII) is present inside LDs, suggesting an active role of LDs in astrocytic antigen presentation. Immunohistochemical analysis of human brain tissue verified the presence of LD-loaded MHCII+ astrocytes in AD individuals. Moreover, we found infiltrated CD4+ T cells to be in close contact with astrocytes, confirming an astrocyte T cell cross-talk in the AD brainConclusions. Taken together, our data show that Aβ pathology drastically affects lipid storage in astrocytes, which in turn modulates the astrocytic antigen presentation, indicating a role for astrocytic LDs in T cell responses in the AD brain.
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| 8. |
- Borgegard, Tomas, et al.
(författare)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 9. |
- Borgegård, Tomas, et al.
(författare)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 10. |
- Brader, Lea, et al.
(författare)
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Effects of a healthy Nordic diet on plasma 25-hydroxyvitamin D concentration in subjects with metabolic syndrome: a randomized, placebo-controlled trial (SYSDIET)
- 2014
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Ingår i: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6215 .- 1436-6207. ; 53:4, s. 1123-1134
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Tidskriftsartikel (refereegranskat)abstract
- At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors. In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (a parts per thousand yen300 g/week, including a parts per thousand yen200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention. At baseline, 45 % had vitamin D inadequacy (< 50 nmol/l), whereas 8 % had deficiency (< 25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes. Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.
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