9 Kommentarer

  1. J T
    4 timmar och 40 minuter. Oj, oj, oj... Blir att låta den stå på vid sidan av när man jobbar...
  2. Anna Delin
    Det verkar som att bara andra halvan av Martijn Katans föreläsning är med.
    I slutet säger han att ökning av mängden kolhydrater (och därmed en minskning av fett)
    inte sänker kolesterolet.

    Föreläsningarna innan: intressant med de nya rönen om de novo lipogenes. Den kan vara stor, speciellt om man äter mycket kolhydrater och den försiggår dels i levern och dels i fettcellerna själva.

    1:31 in finns en bra slide om hur lipolysen stängs av helat av 100 g kolhydrater + 33 g fett. Jag undrar om de gjort samma experiment men bara givit en mycket liten mängd kolhydrater och resten som fett?

  3. Odd Erik Frantzen
    Jeg er, som Anna D, svært interessert i forskjellen i lipolysens effekt med normalt rekommendert karkohydratinntak (50-60% av totalenergi) og LCHF rekommendert karboinntak (5-10% av totalenergi). Hvis ikke dette er avklart er debatten om fettets metabolism ointeressant. Jeg vil også anta at denne forskjellen påvirkes av alder og eller evt. insulinsressistens.
  4. Anna Delin
    Kort sammanfattning av de två första föreläsningarna (Olivercrona och Schwab)

    Tid: 00:07:19
    Olivercrona – en kort introduktionsföreläsning
    Visar bilder på fettmolekyler och hur deras form beror på antalet dubbelbindningar.
    Cellmembran
    Prostaglandiner
    Fatty acids are ligands for nuclear receptors and orchestrate energy metabolism

    Tid: 00:11:22
    Fatty acids in the diet and in the body – food sources and endogenous metabolism U. Schwab, Kuopio University, Kuopio, Finland

    Ger bakgrundsinformation om fettets olika funktioner i kroppen och i maten.
    95% av fettet i maten är i form av triglycerider, 5% som glycerol. Mycket små mängder fosfolipider (lecitin) och kolesterol.
    SFA, MUFA, PUFA, TFA - formen på molekylerna. SFA och TFA är raka, de andra inte. cis vs trans.
    Effects of fatty acids: cardiovascular health, blood pressure, glucose metabolism and insulin sensitivity, blood coagulation, risk of certain types of cancer, low grade inflammation just to name a few.
    Essential fatty acids: C18:2,n-6 (linoleic acid) and C18:3,n-3 (alpha-linolenic acid). Possibly also AA and DHA.
    Elongation and desaturation of fatty acids (in the body)
    In western countries, we have an overload of n-6 fatty acids in comparison to n-3 fatty acids.
    Eicosanoids: blood pressure, renal function, blood coagulation, inflammatory processes, immunological reactions. Eicosanoids have a very short half life 10-20 seconds.
    Exogenous and endogenous pathway of fat: micelles – cholymicrons – lymph
    Tid: 00:22:20: Experiment: lard vs modified lard (position of palmitic acid in the triglyceride is the only difference). Visible effect on cholymicrons but not on VLDL.
    Lipogenesis and lipolysis
    Present nutrition recommendations
    Food sources of fatty acids. PUFA: vegetable oil, dressings, margarines
    FINDIET 2007 study. TFA mainly from dairy products and bakery products.

    Mina kommentarer:
    Schwab nämner inte den eventuella skillnaden mellan TFA (transfatty acids) som finns i mjölkprodukter naturligt och TFA som tillverkats (delvis härdat vegetabiliskt fett).
    Schwab nämnder inte den eventuella skillnaden mellan vegetabiliskt omega-3 och animalt (DHA osv).
    Intressant iakttagelse från FINDIET-studien: I Finland verkar inte PUFA-intaget komma från fisk.

  5. Anna Delin
    Sammanfattning av en föreläsning till.

    Först min egen minisammanfattning: Fett, även mättat fett aktiverar PPAR alpha (finns i levern) som i sin tur ger bättre blodfetter. Glukos aktiverar LXR som ger fettlever, högre TG (dvs sämre blodfetter). LXR kan inhiberas med PUFA.
    Min spekulation: om man äter mycket kolhydrater så kan man förhindra vissa av skadorna genom att äta mycket PUFA.

    00:33:58 – 01:20:24
    Fatty acids and gene expression
    Bart Staels, Univ Lille Nord de France, Inserm U545, Institut Pasteur de Lille

    Nutrient signaling pathways
    Nutrients can change gene expressions
    Epigenetic modifications
    Obesity itself leads to metabolic alterations: reduced glucose tolerance, hyperinsulinemia, hypertension, lipid disorders (high TG, low HDL, LDL moderately elevated or normal)
    Imbalance between nutritional intake and exercise lead to adaption in signal transduction pathways –> transcription factors –> genes –> insulin resistance, obesity, hypertension, lipid disorders
    Vitamin A and D receptors
    Cholesterol can also act on signaling pathways
    Fatty acids and carbohydrates also act on signaling pathways. Proteins = ?
    PPARs and SREBP1 are modulated by different fatty acids
    USF and ChREBP modulated by glucose / carbohydrates. These pathways regulate fat metabolism.
    Nuclear receptor superfamily: endocrine, adopted (e.g., PPAR alpha, beta, gamma) and orphan receptors.
    Role: to help the organism adapt to changing exposure (e.g., new diet).
    Apart from metabolic action, the receptors are also involved in inflammatory responses
    PPAR alpha (found in the liver) is more promiscuous then the other two (PPAR beta, PPAR gamma) and seem to be activated also by SFA.
    Fibrates – fraudulent fatty acids. Activates PPAR alpha
    Activation of PPAR alpha: TG lowering, HDL increase, fatty acid oxidation
    PPAR gamma (adipose tissue): insulin sensitization, glucose lowering, lipid lowering
    PPAR delta (skeletal muscle): lipoprotein metabolism, glucose homeostasis, energy metabolism
    PPAR alpha agonistes correct the atherogenic lipid profile of the metabolic syndrome.
    The atherogenic lipid triad: Low HDL, small dense LDL particles, elevated TG-rich particles
    PPAR alpha activation improves lipid metabolism: FA oxidation goes up, VLDL production goes down, lipolysis goes up, HDL goes up, reverse cholesterol transport goes up. Result: decrease TG, decrease sdLDL, Increase HDL-C
    PPAR alpha knock out mice: feeding high fat diet (lard) demonstrate that PPAR alpha is necessary for many of the effects seen when feeding animals a high fat diet.
    Review article: Barish GD et al (2005), J. Clin. Invest.115:590-97 (siffrorna kan vara fel, det syns dåligt)
    PPAR delta: skeletal muscle, regulates endurance, skeletal muscle differentiation
    PPAR delta: increased HDL-C, improved TG clearance, reduced fasting TG, apoB, LDL-C, insulin, liver fat, urinary, F2 isoprostane
    meal tolerance test: reduced NEFA, increased FA oxidation
    PPAR gamma: adipose differentiation, cytokine production, FFA metabolism
    PPAR gamma activation improves glucose metabolism: muscle glucose uptake, hepatic glucose output. Improved glucose control
    PPAR gamma: effects of glitazones on bone metabolism. Development of bone fractures
    GPR120, PUFA, insulin secretion up, glucagon secretion down, beta cell mass up, gastric emptying down, food intake down.
    PPARs: fatty acid signaling mediators
    Glucose: fatty acid cross-talk pathways
    Glucose and insulin regulation of glycolytic and lipogenic gene expression
    Key transcription factors controlling hepatic glucose and lipid metabolism:
    Glucagon – Foxo1 – Gluconeogenesis, VLDL production
    Insulin signaling – SREPBP1c – glycolysis, lipogenesis
    Glucose signaling – ChREBp – glycolysis, lipogenesis
    (all three processes interact)
    SREBP1 and ChREBP act in concert to stimulate hepatic lipogenesis and TG production
    Identification of the MLX locus as a genetic determinant of plasma TG (Nature Genetics 2008)
    PUFAs (DHA, EPA only?) inhibit SREBP activation
    Feedforward regulation of cholesterol metabolism by LXRs
    Glucose activates LXR
    Cholesterol – LXR – Bile acids, RCT
    Role of LXRs in triglyceride and fatty acid metabolism. LXR can activate formation of fatty liver and triglyceridemia in plasma
    LXR can be inhibited by PUFA

    Frågestund: glukos och särskilt fruktos ger fettlever.
    Lipogenesis stimuleras vid dessa pathways.
    PPAR alpha can also be activated by palmitic acid, not only PUFAs. Probably, the PPAR alpha can sense a general shift in the fat content in the diet.

    Not: experimenten har gjorts med n-3 PUFA av praktiska skäl, så man vet inte hur dessa pathways aktiveras av n-6 PUFA.

  6. Anna Delin
    Sammanfattning av Keith Frayns föreläsning.
    Min kortkorta sammanfattning: De novo lipogenes (DNL), dvs kroppens förmåga att göra fett av glukos och aminosyror, kan vara en mycket viktigare process än vad som antagits hittills.
    DNL pågår både i levern och direkt i fettcellerna. Jag har skrivit in hålltiderna för ställen där det finns i mitt tycke extra intressanta bilder.

    Jag hoppas att Frayn och hans grupp provar att mata sina försökspersoner med LCHF-mat och kollar vad skillnaden blir. Hans matningar nu består av 100 gram kolhydrater och 33 gram fett, per måltid.

    Tid: 01:21:00 – 01:49:35
    Storage and mobilisation of fatty acids in adipose tissue
    Keith Frayn, Oxford University, Oxford, UK

    Physiologist
    Outline of talk:
    Fat storage and mobilization – overview
    Fat storage – pathway and regulation
    Fat mobilization – pathway and regulation
    Dietary fatty acids and adipose tissue
    De novo lipogenesis and adipose tissue

    Nutrionist view: Intake = Expenditure + storage (adipose tissue triacylglycerol)
    Relation between body fat and body weight in 104 women: what people accumulate as they
    grow bigger is essentially body fat. (Webster et al 1984)
    Pathways for fatty acid storage and mobilization. Organs involved: small intestine, liver, adipose tissue, muscle, myocardium, renal cortex.
    ATGL: Adipose triglyceride lipase
    HSL: Hormone sensitive lipase
    LPL: Lipoprotein lipase
    NEFA: Non-esterified fatty acids = FFA: Free fatty acids
    TAG: Triacylglycerol = triglyceride

    Over a 24-hour period we may expect that there is a balance between uptake and release of fatty acids to/from the adipose tissue.

    Direct pathway for dietary fat deposition in adipose tissue: fat – small intestine – cholymicrons via lymphatics insulin – adipose tissue. You can see the chylomicrons straight after a meal: the plasma turns cloudy.

    Physiological action of LPL in adipose tissue.
    TG-rich lipoproteins – FA (LPL) – TAG (inside lipocyte)
    TG-rich lipoproteins – NEFA
    LPL reside on the capillary wall, attached to the endothelial cells
    Cholymicrons present in artery blood. Blood from muscle vein and adipose tissue vein is cleared from cholymicrons.
    LPL action (TG extraction) in adipose tissue. Maximum about 240 minutes after a meal.
    LPL action in adipose tissue over a 24-hour period, 3 meals, 5 hour intervals during the day. Three peaks in the LPL action are seen. The fasting state is not reached between the meals, only during the night.
    Humans who eat 3 meals per day spend most of the time in the fed state.

    Fat mobilization
    ATGL acting on TAG gives DAG + FA
    HSL acting on DAG gives MAG + FA
    MAGL acting on MAG gives glycerol + FA
    MAGL = monoacylglycerol lipase
    Activation of fat mobilization: catecholamines, ANP, BNP, exercise
    Powerfully suppressed by insulin
    The lipolysis pathway: Recommended review: M. Lafontan et al., Trends in Endocrinol. Metab. 2007: 19, 130-7.

    Fatty acid release from adipose tissue. Minimum after about 120 minutes after the meal (100 g carbohydrates, 33 g fat)
    What brings about this pattern? Largely, the insulin concentration. Insulin curve obtains its maximum quite quickly after the meal (around 30 minutes), then declines slowly.
    Adrenaline stimulates lipolysis in human subcutaneous abdominal adipose tissue.
    Fatty acid movements in adipose tissue
    Two pathways: TG from VLDL and cholymicrons vs TG in adipose tissue. These two pathways must interact. Fasting state: net delivery of TG from adipose tissue. In the fed state: this pathway is suppressed by insulin, and there will be a net from of fatty acids from the capillaries into the fat cells. Transcapillary flux.
    Net transcapillary flux of fatty acids in adipose tissue after a mixed meal. Net influx into fat cells starts around 60 minutes after the meal and continues to about 220 minutes after the meal.
    Reference: Frayn et al. 1996 Int. J. Obesity 20, 795-800. Leta på en LKM Summers också.
    Tid 01:35:55. Mycket intressant bild här!! Feeding several meals (3 per day, 5 hour intervals) leads to an upregulation of this process, so that net fat storage occurs continuously over the entire day (about 16 hours consecutively), then during the night (about 8 hours) there is a net outflux of fatty acids from the fat cells. Ref: Ruge et al., JCEM 2009; 94: 1781-1788. Data is for abdominal subcutaneous fat.

    Proportion of the meal fat deposited in adipose tissue.
    Meal 1 15% Meal 2 35% Meal 3 48%

    Adipose tissue fatty acids reflect diet.
    Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake
    n-6 PUFA in diet and adipose tissue correlate: r = 0.5 to 0.6.
    Quite large scatter of points though. Large variance.
    SFA: less strong correlation
    MUFA: distinctly weak correlation or no correlation at all.
    Does that mean than much of the SFA and MUFA in adipose tissue arise from other processes than dietary intake of the same fat?

    De novo lipogenesis and adipose tissue
    The conversion of non-lipid precursors to lipids (fatty acids and cholesterol).
    Glucose – pyruvate – Acetyl CoA –Malonyl CoA – Palmitic acid, Myristic acid, Stearic acid, Palmitoleic acid, Oleic acid.
    It is possible that aminoacids also fit into this pathway.

    Strawford et al., Am. J. Physiol. Endocr. Metab. 2004; 286: E577-88.
    Nine healthy subjects drank labeled 2H2O daily for 8-10 weeks.
    Adipose tissue biopsies at week 5 and 9.
    At week 9, percentage of newly-laid down TG-palmitate that originates from DNL was about 20%. About 10% of all TG.
    This i greater than hepatic DNL, suggesting that DNL within adipose tissue contributes to fat storage.
    Extremely variable from person to person.
    Steraic acid (18:0) content of adipose tissue and insulin sensitivity. Positive correlation, r = 0.54, independent of BMI.
    Tid: 01:43:08
    This is very surprising, since the common knowledge is that the correlation should be inverse.
    Ref: Roberts R et al., Diabetologia 2009; 52: 882-90.
    Since the correlation diet SFA and adipose tissue SFA content is rather weak, what is this telling us?
    There is a strong inverse correlation between insulin sensitivity and adipocyte size. (r = -0.57)
    It turns out, that stearic acid content is related to adipocyte size.
    Tid: 01:44:48
    DNL gene expression
    A conclusion might be that as fat cells enlarge, DNL is down-regulated (or vice versa)
    In vitro experiment: In complete absence of fatty acids, large fat cells full of fat were obtained. The fat cells had access to glucose and amino acids.
    (Bild på detta vid tiden 01:45:50)
    Fatty acid content of these cells: one finds exactly the lipid profile you would expect from de novo lipogenesis (DNL).
    Conclusion: DNL may be more important than has previously been thought.

    Frågestunden:
    With carbohydrate overfeeding, DNL in adipose tissue can actually be greater than hepatic DNL.

  7. Anna Delin
    Kommentar till ännu en av föreläsarna:

    Fatty acids and liver steatosis – pathogenesis and metabolic consequences
    Hannele Yki-Järvinen University of Helsinki, Helsinki, Finland

    Denna föreläsning webcastades inte av någon anledning. Synd, för jag tror att metabola syndromet och sjukdomar/överbelasting i levern hör intimt samman så det hade varit intressant med en sammanfattande föreläsning av någon (eventuellt) fettskrämd person för att se hur de resonerar. Jag letade efter lite publikationer istället. Liver steatosis betyder fettlever och inom lågkolhydratkretsar brukar fruktosen komma upp som en viktig bakomliggande orsak till att denna sjukdom har ökat kraftigt. På andra ställen nämns förutom fruktos även glukos och fett.

    Omega-3 verkar skydda mot fettlever:
    http://www.ncbi.nlm.nih.gov/pubmed/15659701

    Sjukdomen verkar ha att göra med höga insulinnivåer samt låga leptinnivåer.

    Wholehealthsource diskuterar fettlever på flera ställen. Lågkolhydratkost har botat fettlever, rapporterar flera personer där:

    http://wholehealthsource.blogspot.com/2009/06/another-fatty-liver-rev...

    Slutligen, råttor verkar inte kunna få fettlever av mättat fett:

    http://www.nutritionandmetabolism.com/content/4/1/4

  8. Anna Delin
    Tid: 01:50:50 – 02:02:50
    Dietary fatty acids, cholesterol and coronary heart disease
    Martijn Katan, VU University, Amsterdam, The Netherlands

    Första halvan av föreläsningen är inte webcastad, av misstag antagligen.

    Does high LDL cholesterol cause coronary heart disease?
    Almost everything that lowers LDL lowers risk: various classes of drugs, surgery, or diet.
    Most independent experts find the evidence convincing.

    Sources of SFA: meat, butter, cheese, tropical oils (palm oil, coconut oil). MUFA: olive oil, PUFA omega-6: sunflower oil etc, PUFA omega-3: fish oil.

    Meta-analysis of metabolic trials on dietary fatty acids and blood lipids:
    60 trials from 11 countries. 159 diet data points.
    1672 subjects, 70% men, 30% women.
    High quality, well controlled studies
    Ref: Mensink, Am J Clin Nutr 2003
    Effect on blood lipoproteins of replacing saturates with other fatty acids: LDL decreases with 0.5 mmol/L per 10% energy. HDL also decreases very slightly. PUFAs have a bit more effect than MUFAs.

    What do metabolic trials on dietary fatty acids and blood lipids say?
    Replacing 10-15 gram of SFA by PUFA reduces LDL by 0.25 mmol/L.
    That should reduce CHD by 9%. Statistically, by epidemiology.

    Fatty acids and CHD – epidemiology.
    PUFA vs SFA intake and CHD death in epidemiological studies. 327 660 subjects, 6.5 years, 2155 deaths. Result: Total hazard ratio 0.74 (0.61-0.89). This means a 26% reduction of risk.
    Ref: Jakobsen M, AJCN 2009.
    Large error bars in each separate study because it is hard to measure somebodys food intake. Taken together however, the result is clear, there is a clear correlation: more SFA is associated with more CHD deaths.
    (The Finnish ATBC follow-up study has among the smallest error bars.) Min kommentar: är detta den finska mentalsjukhusstudien eller är det något annat?

    Thus: Diets low in SFA and high in PUFA are associated with less CHD.
    Is this causal?

    Clinical trials of replacing dairy and meat fat by PUFA. Names of trials: MRC soy oil, Dayton, Leren and Turpeinen. Ref: Sacks, J Cardiovasc Risk, 1994. Result: A plot of % cholesterol difference vs % CHD difference. All points are in the negative-negative quartile. All studies from the 60-ties(?). By present standards, these are not the best of clinical trials.

    What do the clinical trials of fat and coronary heart disease say?
    Diets low in saturated and high in polyunsaturated FA decrease risk of CHD.
    Pooled relative risk for 8 such trials: risk reduced by 15%, P< 0.05.
    Ref: Harris, 2008.

    Change in CHD incidence when 10-15 grams of SFA is replaced by PUFA: 3 lines of evidence.
    Epidemiology: -13%, RCTs: -8%, predicted from total cholesterol/HDL: -9%.
    Ref: Katan MB, AJCN 2009.
    All three lines of evidence agree quite nicely and give numbers in the same ballpark.

    Summing up:
    Lowring LDL cholesterol lowers CHD risk.
    Replacing SFA by PUFA reduces LDL and the risk of coronary heart disease.

    But, this is science, there can also be some other explanation.

    Frågestund:
    Would you like to comment on replacing SFA by carbohydrates?
    Yes. The evidence there is a lot weaker. The effect on blood lipid is that both LDL and HDL go down, so the ratio doesn’t improve much. There are a few trials, but they didn’t achieve much in reducing cholesterol, I guess because the diets weren’t very palatable. So we don’t really have the clinical trial evidence there. And I’d say by and large that the evidence there is weaker.

  9. Anna Delin
    Min kommentar till Katans föreläsning:

    Det var tyvärr inte ett ord om oxiderade LDL, partikelstorlekar eller mekanismen bakom hur LDL ger CHD och den eventuella rollen av insulin där. Samtliga argument han ger har massakerats sönder och samman (ibland orättvist kanske) på diverse bloggar (hyperlipid, wholehealthsource) så det är poänglöst att repetera allt det ännu en gång.

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