Lipid Metabolism Lecture Notes 2022 PDF

Lipid Metabolism Dr. Victoria Mansour School of Medicine [email protected] COPYRIGHT COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of University of Western Sydney pursuant to Part VB of the Copyrigh...

Lipid Metabolism Dr. Victoria Mansour School of Medicine [email protected] COPYRIGHT COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of University of Western Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice. Learning Objectives Explain how fats get from your food to adipose tissue Describe cholesterol and discuss its transport Describe the reactions needed to completely oxidise a fatty acid to carbon dioxide and water Explain the role of ketone bodies as a metabolic fuel http://personallevelfitness.com/wp-content/uploads/2015/08/Carbsfatprotein-600x450.jpg Lipid digestion and absorption – Food to blood  Dietary fat digestion primarily occurs in the small intestine Bile salts Bile salts Dietary Fat Abbreviations FA – Fatty acids 2-MAGs – 2-monoacylglycerides Emulsion droplet Pancreatic lipase FFA 2-MAGs Micelles Lipid digestion and absorption – Food to blood  Micelles are fat carriers to enterocytes for repackaging and entry to blood Micelles FA 2-MAGs Enterocyte Chylomicrons (CM) Bile salts Lymph Abbreviations FA – Fatty acids 2-MAGs – 2-monoacylglycerides Marieb, E. Human Anatomy & Physiology (7th Edition) (2006) Systemic Circulation Lipid digestion and absorption – Blood to adipose tissue  Once fats are in blood as chylomicrons these TAGs can now enter tissues Glucose Glycerol CM LPL FA ADIPOSE TISSUE TGs CM Remnant Systemic Circulation LIVER Abbreviations CM – Chylomicron TGs - Triglycerides FA – Fatty acids LPL – Lipoprotein lipase Fat & Cholesterol transport molecules  Lets look at some players first  Chylomicrons  Produced by enterocytes  Chylomicron remnants  higher cholesterol content cholesterol  Very Low Density Lipoproteins (VLDL)  Produced by the liver  Intermediate Density Lipoproteins (IDL)  Derived from VLDL breakdown  LDLs  Derived from IDL breakdown  High cholesterol content  HDLs  Empty shells produced by the liver Marieb, E. Human Anatomy & Physiology (7th Edition) (2006) Fat & Cholesterol transport LDL IDL Dietary Fat Intestines Chylomicrons Tissues Chylomicron remnants Bile HDL Liver VLDL Endogenous lipids Glycolysis  We have seen how fats are obtained and stored from dietary sources Glucose Glycogen G-6-P AA FATTY ACID SYTHESIS Glycogenolysis  But in some circumstances we need to make FA  The same process is used for FA storage, but where endogenous FA come from?? Galactose Cytosol Glycerol FA DHAP Fructose G-3-P Lactate Pyruvate Amino acid catabolism Acetyl-CoA OAA  3 main sources  Glycolysis (& Krebs)  Fatty acids  Amino acids Abbreviations AA – Amino acids G-3-P - Glucose-3-phosphate G-6-P – Glucose-6-phosphate DHAP - Dihydroxyacetone phosphate FA – Fatty acids OAA - Oxaloacetate Fatty acid oxidation Citrate Acetyl-CoA OAA Mitochondrial matrix Endogenous Lipids Abbreviations TAGs - Triacylglycerides FA – Fatty acids LPL – Lipoprotein lipase FAS – Fatty acid synthase VLDL – Very low density lipoprotein  So how is Acetyl-CoA used to make FA Acetyl-CoA Acetyl-CoA Carboxylase Malonyl-CoA Malonyl FAS Condensation FAS Acetyl Reduction to alcohol  FA synthesized  TAGs  VLDL  FA released by LPL  Already seen how storage takes place Dehydration = double bond Reduction = saturation BUT HOW DO CELLS USE FAs FOR ENERGY?? FAS Fatty Acid Oxidation Carnitine  So our sources of FA for energy come from  Endogenous production  Chylomicrons  Dietary fats  Release from adipose tissue  Prior to β-oxidation some steps are required  Entry into cells  FA activation – short and med FA vs. long FA  Transfer to Mitochondria OCTN2 FA FA Cytosol FA-CoA Carnitine Outer membrane CPT1 Intermembrane space O-acyl carnitine (FA+carnitine) CACT  Once in the mitochondria let β-oxidation begin Abbreviations FA – Fatty acids Co-A – coenzyme A CPT1 – carnitine palmitoyl transferase 1 CPT 2 – carnitine palmitoyl transferase 2 CACT – carnitine:acylcarnitine translocase OCTN2 – carnitine transporter Inner membrane CPT2 O-acyl carnitine (FA+carnitine) CoA Mitochondrial matrix FA-CoA Carnitine Fatty Acid Oxidation  Now remember FA synthesis  Reduction  dehydration  reduction  This is the reverse for fatty acid breakdown   Oxidation  hydration  oxidation Fourth step is cleavage  Following cycle is for saturated FA  Oxidation of unsaturated and polyunsaturated FA requires further enzymes  Odd carbon FA can also be oxidised  B-oxidation of a FA molecule yields  FADH2 So what is  NADH our fate??  Acetyl-CoA Garret and Grisham, Biochemistry 4th edition (2010) Fatty Acid Oxidation  Fate of Acetyl-CoA  Amino acid biosynthesis (will cover this in another lecture)  Ketone synthesis (next slide)  Enters Krebs cycle   Produces ATP Produces additional NADH and FADH2  Electron transport chain  Thus for one FA molecule (palmitate – C-16) Fats Palmitate C-16 FA Cytosol Mitochondria NA B-oxidation 7 rounds = 7 NADH (17.5 ATP) 7 FADH2 (10.5 ATP) 28 ATP - 2 ATP* 26 ATP *FA to FA-CoA conversion NOTES 1 NADH produces 2.5 ATP 1 FADH2 produces 1.5 ATP NET ATP YIELD Krebs (8 acetyl-CoA) 8 ATP 24 NADH (60 ATP) 8 FADH2 (12 ATP) 80 ATP 106 ATP Ketogenesis Glycolysis  Occurs in the liver – mitochondrial matrix Glucose  During states of starvation, low carb intake or diabetes  High levels of FA are oxidised   Acetyl-CoA  This inhibits pyruvate dehydrogenase (A) and activates G-6-P pyruvate carboxylase (B)  DHAP Acetyl-CoA from FA breakdown in liver  Ketogenesis G-3-P FA Pyruvate B Fatty acid oxidation Abbreviations AA – Amin acids G-3-P - Glucose-3-phosphate G-6-P – Glucose-6-phosphate DHAP - Dihydroxyacetone phosphate FA – Fatty acids Cytosol A Ketogenesis Acetyl-CoA Oxaloacetate (OAA) Mitochondrial matrix Citrate Ketogenesis  Occurs in the liver – mitochondrial matrix  During states of starvation, low carb intake or diabetes  High levels of FA are oxidised   Acetyl-CoA  This inhibits pyruvate dehydrogenase (A) and activates pyruvate carboxylase (B)  Acetyl-CoA Thiolase Acetoacetyl-CoA Acetyl-CoA from FA breakdown in liver  Ketogenesis HMG-CoA Importance of Ketone bodies  Is an avenue to produce alternate energy metabolites for many tissues (aka ketone bodies)  Heart muscle and kidney cortex  Brain Acetoacetate Normal substrates β-Hydroxybutyrate dehydrogenase During starvation  Can be transported in blood to peripheral tissues  Acetyl-CoA Converted to Acetyl-CoA for use in Krebs cycle Acetone β-Hydroxybutyrate Clinical relevance: Nutrition and Health  Obesity  Energy Intake > Energy expenditure  Excess energy (carbs/fats) are packaged as TAGs and transferred to adipose tissue  Factors that can all contribute to Obesity include  Disturbances in physiological mechanisms that regulate food intake and energy metabolism  Genetics, microbiome, lifestyle, environmental and psychological factors Overweight & obesity Overview - Australian Institute of Health and Welfare (aihw.gov.au) Clinical relevance: Nutrition and Health Carnitine  Obesity  Energy Intake > Energy expenditure  Excess energy (carbs/fats) are packaged as TAGs and transferred to adipose tissue  Factors that can all contribute to Obesity include   Disturbances in physiological mechanisms that regulate food intake and energy metabolism Genetics, microbiome, lifestyle, environmental and psychological factors  Primary Carnitine Deficiency (OCTN2)  Carnitine palmitoyl transferase (CPT1) Deficiency  Carnitine-acylcarnitine translocase (CACT) Deficiency  Carnitine palmitoyl transferase (CPT2) Deficiency  All four disorders  prevent FA oxidation  reduced energy from FA OCTN2 FA FA Cytosol FA-CoA Carnitine Outer membrane CPT1 O-acyl carnitine (FA+carnitine) Intermembrane space Inner membrane CACT CPT2 O-acyl carnitine (FA+carnitine) CoA Mitochondrial matrix FACoA Abbreviations FA – Fatty acids Co-A – coenzyme A CPT1 – carnitine palmitoyl transferase 1 CPT 2 – carnitine palmitoyl transferase 2 CACT – carnitine:acylcarnitine translocase OCTN2 – carnitine transporter Carnitine Clinical relevance: Nutrition and Health  Obesity  Energy Intake > Energy expenditure  Excess energy (carbs/fats) are packaged as TAGs and transferred to adipose tissue  Factors that can all contribute to Obesity include  Disturbances in physiological mechanisms that regulate food intake and energy metabolism  Genetics, microbiome, lifestyle, environmental and psychological factors  Primary Carnitine Deficiency (OCTN2)  Carnitine palmitoyl transferase (CPT1) Deficiency  Carnitine-acylcarnitine translocase (CACT) Deficiency  Carnitine palmitoyl transferase (CPT2) Deficiency  All four disorders  prevent FA oxidation  reduced energy from FA  Lipid pathways can be targets for drugs TAG breakdown  Storage of lipids in adipose tissue can arise from  Exogenous and endogenous sources  Fatty acid synthesis occurs in the liver   Adipose tissue Galactose Glucose Glycogen G-6-P Glycogenolysis/glycogenesis Starting material can be derived from Glycolysis (& Krebs), Fatty acid oxidation and amino acid catabolism Packaged into TAGs  VLDL for delivery to tissues FA Glycerol DHAP Fructose G-3-P  Fatty acid oxidation   Requires activation and transport into mitochondria before used as energy source Provides much more energy than carbohydrates Fatty acid oxidation  Ketone bodies can be produced as alternate energy depending on body demand/health status  Influences on fatty acid metabolism can have an impact on health Fatty acid synthesis Lactate Pyruvate Acetyl-CoA Ketone bodies ATP Electron transport chain Krebs Cycle Glycolysis/gluconeogenesis Summary Summary Liver (FA & cholesterol synthesis & breakdown) Bile HDL CM remnants Dietary Fat TGs digested to release FAs Intestines (absorption of FAs) CMs Repackaged into TGs Lymphatics Systemic circulation LDL IDL Most tissues = energy fuel Adipose tissue = fat storage VLDL Thank you  Lecture feedback Questions Contact Details Dr. Victoria Mansour Lecturer in Medical Education Medical Education Unit PBL Convener Western Sydney University [email protected] Phone 02 46203751 Office 30.3.14 Available Mon, Tues, Thurs & Fri Links and Resources  Garret and Grisham, Biochemistry 4th edition (2010)  Boron and Boulpaep, Medical Physiology 2nd edition (2012)  Guyton and Hall, Textbook of Medical Physiology 13th edition (2016)  Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 30.2, Each Organ Has a Unique Metabolic Profile. Available from: https://www.ncbi.nlm.nih.gov/books/NBK22436/  Disorders of carnitine transport and the carnitine cycle. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2557099/ Extra reading for interest  http://www.newbornscreening.info/Parents/fattyaciddisorders/CTD.pdf