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Advanced Nutrition Lipids metabolism MargiAnne Isaia, MD MPH LIPIDS LIPID OXIDATION: Cellular transport of fatty acids uses Carnitine shuttle Beta oxidation of fatty acids is a complete oxidation. The end result of this oxidation is Acetyl CoA. Well fed state : Fasting, starvation, exercise: - fatty acids come from diet - fatty acids come from storage (adipose) If SCTG consumed : more energy production (direct transfer, more rapid oxidation) LCFA n-3 and n-6 more rapidly oxidized than SFA SCTG short chain triglycerides LIPIDS MOBILIZATION OF FFAs 1. Fasting, starvation, exercise -Glucagon and Epinephrine are released -these hormones stimulate Hormone-Sensitive Lipase (HSL) HSL breaks down TAG to FFA and glycerol 2. FFAs bound to albumin transported to metabolizing tissue Glycerol transported to the liver for gluconeogenesis. FFAs- activated to FFA acylCoA – taken up by mitochondria to be oxidized LIPIDS LIPIDS CARNITINE SHUTTLE Carnitine is synthesized from Lysine (LYS) and Methionine (MET) SCFA, MCFA do not use carnitine shuttle. Carnitine and three enzymes: CPT I and II, CAT are involved in the transfer Carnitine deficiency- impaired oxidation of FAs- diseases associated with hyperglycemia. Carnitine deficiency: -primary (systemic) genetic origin, developed from mutation of carnitine transporter OCTN2 (progressive cardiomyopathy skeletal myopathy, hypoglycemia, hyperammoniemia) - secondary to many genetic / acquired disorders (episodic hypoketotic hypoglycemia, starting in infancy) Carnitine supplementation : supposed to increase energy production, because it facilitates the FA transport into mitochondria for oxidation, sparing glycogen from the muscles during exercise; could mitigate lactate production Studies: carnitine is not a ergogenic aid to increase sport performance. LIPIDS b OXIDATION Oxidation of FAs result in removal of AcetylCoA (2 carbon) molecule at a time 12C fatty acid will produce 6 AcetylCoA molecules Energetics of FA oxidation even chain FA – end product Acetyl CoA – enters TCA cycle odd chain FA – 3 C residue remains (Propionyl CoA) Propionyl CoA is the only part of FA that is glucogenic. B vitamin, Biotin = coenzyme for Propionyl CoA carboxylase Vitamin B12 = coenzyme for Methylmalonyl CoA isomerase. MMA = Methylmalonic Acid – byproduct of Methylmalonyl CoA. hMMA + hHomocysteine level = Vitamin B 12 deficiency h Homcysteine level + normal MMA= folate deficiency LIPIDS TYPE OF FFAs AND OXIDATION Effects of FFAs with greater retention - predispose to obesity - alter membrane fluidity (receptor-ligand) - influence eicosanoid metabolism SCFAs, MCFAs faster oxidation - direct absorption - do not require chylomicrons for transport - do not use Carnitine shuttle for oxidation PUFAs faster oxidation than SFA - faster mobilization from adipose preferred substrate for HSL - hepatic FA oxidation bypasses first step in oxidation (+) oxidative enzymes (induction) - mitochondrial entry preferred uptake for by Carnitine shuttle LIPIDS PEROXISOMAL OXIDATION - primarily for VLCFA (>20 C) -a modified form of b oxidation - first dehydrogenation reaction uses FAD -Hydrogen is not transferred to ETC, but to molecular O2, forming H202 -This is disposed by catalse Purpose is to fragment VLCFA prior to b oxidation Then b oxidation 2 coenzymes: NAD & FAD NAD/NADH g 3ATP FAD/FADH g 2 ATP LIPIDS LIPID PEROXIDATION Lipids g oxidized by Reactive Oxygen Species (ROS: superoxide, OH-, singlet oxygen, HOCL) Oxidative stress g circumstances that increase oxidant exposure result in increased formation of ROS (chemicals, drugs, decreased antioxidant capability) Free radicals (ROS) look for H in the body Lipids are high in hydrogen atoms Unsaturated lipids – more H atoms unstable (C=C highly unstable, FA becomes more reactive) Free radicals damage FFA, DNA, proteins Phases in formation of free radicals: initiation, propagation, termination ROS balanced with anti-oxidants in healthy people. LIPIDS LIPID PEROXIDATION Lipid peroxidation (partial oxidation) occurs with PUFA End products are aldehydes and hydrocarbon gases - TBARS, MDA are markers of lipid peroxidation: useful in research : TBARS in blood, urine, after fish oil administration Membrane integrity affected - permeability increases - receptor–ligand interaction decreases - enzyme activity decreases. TBARS = THIOBARBITURIC ACID REACTIVE SUBSTANCE MDA = MALON DIALDEHYDE LIPIDS LIPID PEROXIDATION Vitamin E – terminator of peroxidation (chain-breaking antioxidant because it donates a hydrogen atom for lipid radicals) Glutathione peroxidase - effective in reducing lipid peroxides (selenoperoxidases) PUFA/Vitamin E ratio indicates peroxidative capacity - Vegetable oilsg good PUFA/Vitamin E ratio - Fish oilg high PUFA, low vitamin E PUFA and vitamin E must be together Important: limit PUFA intake (<10% of total energy from PUFA) LIPIDS FA BIOSYNTHESIS SFA synthesized in the cytoplasm Enzyme: Fatty Acid Synthetase complex Site: liver (primarily), adipose (minor) Acethyl CoA--building block Rate limiting enzyme is Acethyl CoA carboxylase - fat free diet: (+) enzyme (induction = up-regulation) - high PUFA diet: (-) enzyme (repression = down-regulation) Acetyl CoA (2C) ggggg palmitic acid (16C) (enzyme complex) LIPIDS FA BIOSYNTHESIS End product is Palmitic Acid ( C16:0) Used for energy/storage Chain elongation and desaturation can occur Location: ER membranes Desaturase D9, D6, D5, D4 ( enzymes specific for double bond position) Elongase helps in synthesis of VLCFA (brain, nervous system) EFFECTS OF DESATURASE AND ELONGASE ON ESSENTIAL FATTY ACIDS n-7 EFA n-9 EFA n-6 EFA n-3 EFA Palmitic 16:0 Stearic 18:0 Palmitoleic 16:1 n-7 Oleic 18:1 n-9 Linoleic 18:2 n-6 a- linoleic 18:3 n-3 18:2 n-9 g- Linolenic 18:3 n-6 18:4 n-3 18:2 n-7 20:2 n-9 Dihomo- g linolenic 20:3 n-6 20:4 n-3 18:3 n-7 Eicosatrienoic 20:3 n-9 Arachidonic 20:4 n-6 Eicosapentaenoic 20:5 n-3 22:3 n-9 Docosatetraenoic 22:4 n-6 22:5 n-3 22:5 n-6 Docosahexaenoic 22:6 n-3 D9 desaturase D6 desaturase 16:2 n-7 elongase D5 desaturase elongase 20:3 n-7 D4 desaturase LIPIDS DESATURASE PATHWAY 18:2 n-6 (Linoleic Acid) and 18:3 n-3 (a-Linolenic Acid) n-3 and n-6 cannot interconvert affinity for desaturases: n-3 > n-6 > n-9 For the same quantity of substrate available first will be used n-3 from n-3 FA will result n-3FA from n-6 FA will result n-6 FA EFA: For Unsaturated FA- desaturases are common Eicosatrienoic acid C20:3 n-9 – maker to asses Essential Fatty Acids ( n-9 EFA not physiologically important) Arachidonic acid (C20:4 n-6) pro-inflammatory effect EPA ( C 20:5 n-3) – anti-inflammatory effect DHA ( C 20:6 n-3) – anti-inflammatory effect Arachidonic acid must be balanced with EPA/DHA LIPIDS DESATURASE PATHWAY - excess of n-6 FA will reduce n-3 FA metabolism - nutritional implications -18:1 n-9 level needs to be very high to compete with n-6 and n-3 In EFA deficiency C18:1 n-9 converted to 20:3 n-9 (eicosatrienoic acid = biomaker for EFA status) During hydrogenation positional isomers of FA are formed (Trans FA) Trans FA compete with EFA and SFA for desaturase and elongase Diet impacts desaturase enzymes LIPIDS DESATURASE PATHWAY Diet impacts desaturase enzymes activity (American diet – too much n-6 FA Enzymes will convert Linoleic Acid to Arachidonic Acid) D6 desaturase- increased activity: - fat-free diet - protein and EFA deficiency - Insulin D6 desaturase- decreased activity: - alcohol - Glucagon, Epinephrine, NE, Thyroxine, Glucocorticoids, Diabetes (catabolic states) LIPIDS CHOLESTEROL SYNTHESIS Liver g site for endogenous synthesis of Cholesterol Acetyl CoA precursor HMG CoA reductase is rate limiting enzyme: (3 Hydroxy-3 Methyl-Glutaryl Coenzyma A reductase)) Body regulates the Cholesterol synthesis: - feedback (-) (h cholesterol – inhibits the enzyme activity) - hormonal: Insulin (+) - via Sterol Regulatory Element Binding Protein (SREBP) down-regulates enzyme expression STATIN Drugs – competitive inhibitor of HMG–CoA Reductase - decrease Cholesterol synthesis - interfere with other pathway (CoQ10) CoQ10 (ubiquitin) involved in energy metabolism Statin drugs side effects i CoQ10, extreme fatigue Maybe: take CoQ10 as supplement, if under Statin drugs. LIPIDS REFERENCES 1. Shils M et al, Modern Nutrition in Health and Disease, 10th Edition 2. www. Pubmed.org QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS? QUESTIONS?