MC1 Metabolism Introduction - Dietary Lipids and Storage (PDF)

Metabolism MC1 Introduction to metabolism: Lipids and dietary lipids Dr Matthew Conner  Content MC 1 Introduction to metabolism (review of TCA and ETC): Lipids and dietary lipids MC 2 Lipid catabolism MC 3 Carbohydrate metabolism and lipid biosynthesis MC 4 Protein m...

Metabolism MC1 Introduction to metabolism: Lipids and dietary lipids Dr Matthew Conner  Content MC 1 Introduction to metabolism (review of TCA and ETC): Lipids and dietary lipids MC 2 Lipid catabolism MC 3 Carbohydrate metabolism and lipid biosynthesis MC 4 Protein metabolism MC 5 Pentose phosphate pathway Metabolism : Metabolism Catabolism Catabolism FOOD Complex Polymers FATS Carbohydrates Proteins Polymers/oligomers Fatty acids Mono Amino glycerols saccharides acids Monomers Energy and metabolic building blocks Liver and Muscle Muscle Lypolysis Glycogen Pyruvate Acetyl-CoA Citric acid cycle /ATP Catabolism and Anabolism TCA, Kreb’s  Catabolism and Anabolism Carbohydrate Lipid metabolism catabolis Protein m Lipid metabolism biosynthe Pentose sis phosphate pathway TCA, Kreb’s Cycle In mitochodria ETC and ATP production  Catabolism and Anabolism TCA, Kreb’s Cycle In mitochodria ETC and ATP production TCA, Kreb’s Cycle, Citric Acid Cycle TCA, Kreb’s Cycle, Citric Acid Cycle TCA, Kreb’s Cycle, Citric Acid Cycle What’s the point?  To make adenosine triphosphate The bonds between adenosine and phosphates are highly strained bonds So are a form of chemical potential energy Mitochondria Energy production About the size of a bacterial cell (2 m) Aerobic respiration takes place to extract energy,synthesising ATP Tricarboxylic acid cycle (TCA) occurs here Electron transport chain Electron transport chain Electron transport chain Complex I (NADH coenzyme Q reductase; labeled I) accepts electrons from the Krebs cycle electron carrier nicotinamide adenine dinucleotide (NADH), and passes them to coenzyme Q (ubiquinone; labeled Q), which also receives electrons from complex II (succinate dehydrogenase; labeled II). FADH2 is also reduced to FAD+ at complex II. Q passes electrons to complex III (cytochrome bc1 complex; labeled III), which passes them to cytochrome c (cyt c). Cyt c passes electrons to Complex IV (cytochrome c oxidase; labeled IV), which uses the electrons and hydrogen ions to reduce molecular oxygen to water to remove the electrons (otherwise where would electrons go? It would clog up. ATPsynthase  ECT video ATPsynthase video  1. Proton gradient 3. ADP + Inorganic phosphate. 2. ATP 4. ATP synthase Remember this slide from transport lecture? Knowledge Organiser/ Mind Map TCA, Kreb’s Catabolism and Anabolism Catabolism and Anabolism The integration of metabolism is revealed by looking at the processes that predominate when the organism is in extremis For metabolism these are the The fed state (0-4 hours after eating) The fasted state (4-12 hours after eating) The starved state (12 hours and onwards without eating) Fed Fasted  The Fed state (0-4hrs) Gut Liver Brain Lipids Glucose Amino acids Muscle Adipose Blood glucose levels enough to supply energy for a few minutes The Fasted state (4-12hrs) Liver Glucose Brain (from Liver Glycogen) Free Fatty acids (FFA) mGlycogen FFA Muscle Adipose Glycogen stores enough to supply energy for about one day The Starved state (12/20hrs onwards) Liver GLUCOSE Brain From gluconeogenesis Ketones Lactate Free Fatty acids (FFA) Amino acids and glycerol FFA Muscle Adipose Fat stores enough to supply energy for weeks Protein (from muscle) is also a good supply of energy Estimated energy stores in humans  Glycogen A polysaccharide An energy store A homopolymer (all the subunits are the same) Glycogen is a homopolymer of glucose Glycogen is a highly branched molecule HOCH2 α-1,6 glycosidic bond O 4 1 …..O OH O HOCH2 HOCH2 6 CH2 O O OH O 4 1 4 1 4 1 …..O OH O OH O OH ….. O OH OH OH glycosidic bonds are present once in 10 units  Glycogen is a highly branched molecule Glycogenin core Open helix structure n is the gluccose storage molecule in animals points are every 8 - 10 linked a -(14)- glucose units nt branching Increases solubility- ugar units more readily accessible elix formed by a-(14) links best suited for this units are more readily mobilised ound in: ng term storage. Important for maintaining blood [glucose] Important source of energy for quick bursts of activity FAT (TRIGLYCERIDE) Fat has more energy but is less efficient/readily used. NB: Heart primarily used beta-oxidation of fatty acids for energy as the O2 supply is high  Complexity: Many interconnected process occur at same time in different organs and tissues Dietary lipids  Lipids A family of compounds that includes – Triglycerides (fats & oils) Fats: lipids that are solid at room temperature Oils: lipids that are liquid at room temperature – Phospholipids – Sterols (cholesterol). Focus on Triglycerides  Triglycerides or Triacylglycerols  Fatty acids are rarely free molecules.  Fatty acids are primarily stored as fuel molecules In combination with Glycerol  Biosynthesis of triacylglycerol is complex and requires a number of intermediary steps  And precursor molecules formed during metabolism.  We shall just consider the simple linkage of fatty acids directly to Glycerol.  A triglyceride is formed when one glycerol molecule joins with three fatty acids to produce a triglyceride and water  Water is eliminated (condensation reaction)  Fatty Acids There are many different Fatty Acids but all have same basic structure. They are made of chains of carbon with a methyl group at one end (CH3) and a carboxyl group at the other end (COOH). What makes one fatty acid different from another is the length of the aliphatic (linear – not ring) carbon chain  Triglycerides or Triacylglycerols + H20 + + + H20 + + H20 Glycerol + 3 Fatty Acids = Triglyceride + Water Chemical Structure of Lipids Chemical Structure of Lipids Fatty acids bind to Glycerol by the formation of ester bonds (Esterification) Esterification is a reaction between an acid (COO-) and an alcohol (OH) OH O OH - C O OH Fatty Acid +H + Glycerol O O C Acyl Glycerol HHO (H2O) R-C=O: Acyl 51 group  Triacylglycerols can be simple: Triacylglycerols (Fats) are non-soluble in H2O because they are non-polar 52 Or Complex: Most natural fats contain a complex mixture of individual triglycerides. 53 Dietary lipids Triglycerides and cholesterol from the diet gets emulsified by bile acids in the intestine to form micelles. Bile acids are themselves made from cholesterol.  Occurs together FAs and MAG with bile salts= micelles and makes foe easier passage of FAs and MAG into cells This results in 2 free fatty acids + 1 monoacylglycerol which can enter intestinal mucosal cell Once absorbed to the intestinal mucosa cells the fatty acids and monoacylglcerol are combined to re-form triacylglycerolsand packaged into chylomicrons Chylomicrons (lipoprioteins) While circulating in blood, chylomicrons exchange components with high-density lipoproteins (HDL). The HDL donates apolipoprotein C-II (APOC2) and apolipoprotein E (APOE) to the nascent chylomicron and, thus, converts it to a mature chylomicron (often referred to simply as "chylomicron"). Upon arrival in adipose tissue and muscle cells, lipoprotein lipase cleaves the triacylgycerols to free fatty acids and glycerol. Fatty acids are taken up by these tissues and glycerol is transported to liver or kidneys FA delivery to the adipocyte(1) lipoprotein lipase molecules on the endothelial surface of the capillary bind to a chylomicron and hydrolyse the triacylglycerol (Triglyceride) portion of the particle. (2) FAs released by this process then enter the adipocyte and are esterified into triacylglycerol or bind to albumin with the capillary space becoming part of the albumin–FA complex. These can either enter the adipocyte or systemic circulation. (3) Triacylglycerol within the adipocyte can be hydrolysed to FAs by hormone-sensitive lipase or triacylglycerol lipase. These FAs are either re-esterified within the adipocyte or released into the capillary to bind with albumin. Main effects of Insulin and glucagon Insulin Glucagon Reduces blood glucose levels Increase liver glycogen synthesis Stimulates glycogen breakdown Increases glycolysis Stimulates gluconeogenesis Increase glucose uptake in peripheral tissues Stimulates protein breakdown Increase amino acid uptake and protein synthesis inhibits protein breakdown Inhibits lipogenesis Increases lipogenesis Activates lipolysis and ketone synthesis inhibits lipolysis How is fat made from glucose MC3 lecture  Adipose tissue depots Subcutaneous Vs. visceral adipose tissue  Subcutaneous fat - Formed from the mesoderm - Perhaps more simply required for fat storage and insulation than visceral fat. - Now known to have many secreted adipokines  Visceral (omental) fat Releases adipokines (is an endocrine organ?)  OK, so fat is everywhere, it’s mainly these adipocytes with macrophages and vascular cells and is there for the storage of food, insulation and protection of important areas.  Endocrinology Fat cells are part of the endocrine system What is a hormone ? Chemical messengers released from one tissue, carried in the circulation & producing a specific, receptor-mediated change in another tissue.  Adipose-derived hormones Lots of these (100s from spectroscopic analysis and more discovered all of the time; roles vary and are not always clear) Leptin (increased in obesity, central and peripheral effects; causes negative outcomes) Adiponectin (decreased in obesity therefore you lose the  Adiponectin 244 amino acid protein with several domains. Secretion is caused by and correlates with insulin levels Adiponectin is REDUCED with obesity and promotes INSULIN SENSITIVITY. Thought to promote glucose uptake (in muscle) and inhibit gluconeogenesis (liver) whilst promoting fatty acid oxidation (in both). Similar, complementary (and often additive) effects to leptin. It looks like this:  Leptin 16kDa (166 amino acids) protein Important roles in METABOLISM and FEEDING A random mouse mutation of the leptin gene (Jackson labs in the 50s) was massively obese.  Leptin (satiety signal) Leptin acts on tyrosine kinase receptors in the hypothalamus with many physiological, anorectic effects (including opposing the orectic anandamide and neuropeptide Y ) Leptin is increased in obesity with central and peripheral  Human leptin role? Effects of recombinant human leptin treatment in a patient with congenital leptin deficiency. (A) Before treatment. (B) After treatment. Leptin: a pivotal regulator of human energy homeostasis. Farooqi IS, O'Rahilly S. Am J Clin Nutr.  Human leptin role? It is interesting that in general, anti- satiety proteins “don’t really work very well” in humans. But…Leptin is increased in obesity and this means that obese people are less sensitive to leptin and therefore have less of a satiety signal. Why not? In humans, eating behaviour is a wide network including social triggers (advertising, social HUNGRY? 75 HUNGRY?  Other Adipokines Resistin – 118 aa cys-rich secreted protein. Correlates with obesity. Possible role in T2DM Visfatin – enzyme in high levels in obesity and visceral fat. Possibly insulin-sensitising. Chemokines – Many are also adipokines Non-peptide – Fatty acids, cholesterol, steroid hormones and more. Bind to membrane bound lipases on muscle and adipose cells hydrolised to: free Fatty acids and monoacylglycerol, transported across cell membrane Once inside adipose cell are reformed to Triacylglycerols! Video: Overview of lipid processing Main effects of Insulin and glucagon Insulin Glucagon Reduces blood glucose levels Increase liver glycogen synthesis Stimulates glycogen breakdown Increases glycolysis Stimulates gluconeogenesis Increase glucose uptake in peripheral tissues Stimulates protein breakdown Increase amino acid uptake and protein synthesis inhibits protein breakdown Inhibits lipogenesis Increases lipogenesis Activates lipolysis and ketone synthesis inhibits lipolysis metabolism mind map Catabolism and Anabolism  Next lecture MC 2 Metabolism Lipid catabolism