Fat Metabolism Flashcards
How much fat do most people store and where?
- Most energy in the body is actually stored in fats – most people store between 5 and 20 kg of fat in their adipose tissue
What are important stores of energy in the body and why?
- Lipids and their derivatives (ketone bodies) are important stores of long-term energy.
- Lipids: great storage – high density energy in relatively small space and limitless storage capacity.
Where and when does lipolysis occur?
- Lipolysis occurs mostly in adipose tissue.
- Only occurs in aerobic conditions – needs oxygen
What is the main enzyme that regulates lipolysis? What is it activated/inhibited by? What controls its switching, and what can block this?
- Hormone-sensitive lipase (HSL: aka diglyceride lipase)
o Activated by adrenaline and noradrenaline (epinephrine and norepinephrine)
o Inhibited by insulin
o Switching is controlled by cAMP signalling that activates kinases to phosphorylate HSL which becomes active and degrades triglycerides to fatty acids.
o Insulin blocks cAMP activity and keeps HSL de-phosphorylated (inactive)
Why must there be more than one enzyme controlling lipolysis?
- Experiments with knock out mice with no active HSL still are able to break down lipids…there must be more control!
What other enzyme has been identified as controlling lipolysis? What does it do and how is it regulated?
Adipose triglyceride lipase (ATGL)
o Breaks down triglycerides to diglycerides and fatty acid
o An important pre-cursor to HSL which is able to free up fatty acids from lipids.
- ATGL is regulated separately from HSL and is regulated and activated by glucagon via cAMP
- ATGL is also found in low levels in other tissues such as heart.
Why are free fatty acids dangerous and how do we get around that?
- Free FA in blood are toxic so have to be transported attached to albumin.
How are fatty acids converted to acetyl Co-A?
- The conversion of FA to acetyl CoA is a 3-step process:
1. Conversion of FA -> fatty acyl-CoA on outer mitochondrial membrane
o (enzyme: acyl CoA synthase [ACS])
o uses ATP -> AMP - Fatty acyl CoA transported into mitochondrial matrix by the Carnitine shuttle
- Beta-oxidation of fatty acyl-CoA to acetyl CoA + NADH/FADH2 (Krebs cycle….)
What happens in the Carnitine Shuttle?
- Fatty acyl Co-A is linked to a carnitine molecule (enzyme – carnitine acyl-transferase I [CATI]). CoA is released.
- Acyl-carnitine complex transferred across IMM into the matrix (enzyme – translocase)
- Acyl-carnitine reacted with CoA to produce acyl-CoA inside the matrix and carnitine shuttled back out (enzyme – carnitine acyl transferase II, CATII)
When does the main regulation of FA metabolism occur? How is transport of FA into the mitochondria inhibited/activated?
- Main regulation of FA metabolism occurs during the carnitine shuttle.
- Transport of FA into the mitochondria:
- Inhibited by malonyl Co-A (a product of the conversion of acetyl CoA -> fat in fat synthesis to prevent futile cycling)
- Activated by glucagon through cAMP signalling to transport more fatty acyl-CoA into the mitochondria to be converted to energy.
What are the short and long term methods of controlling FA breakdown?
- Short-term control: o allosteric activation/inhibition o malonyl CoA and glucagon - Long-term control: o changes in gene expression of o CAT1/CPT1
What is the last step of FA breakdown?
- The last step of FA break down is the actual removal of carbons from the long chain of the FA to give acetyl-CoA with each 2 carbons removed.
How many reactions are there in each cycle of beta oxidation of acyl-CoA? What happens with each cycle? What does unsaturated FA require?
- A cycle of 4 reactions and with each cycle the FA loses 2 carbons in the form of one acetyl CoA molecule. (How many cycles of break down does palmitic acid, a 16-carbon fatty acid, undergo?)
- Unsaturated FA require more enzymes.
Which enzymes break down FA?
- FA are broken down by a number of enzymes, mostly dehydrogenases (remove hydrogen)
Which four reactions does each cycle of FA breakdown involve? What are the products? Where does beta oxidation occur?
- Each cycle involves oxidation, hydrolysis, oxidation, thiolysis (“OHOT”)
o In the process, 1 NADH and 1 FADH produced per cycle - Products of β-oxidation of a C-16 FA (palmitic acid):
o ? acetyl Co-A – TCA cycle – 96 ATPs
o ? NADH – TCA cycle – 21 ATPs
o ? FADH - TCA cycle – 14 ATPs – ? total ATPs from 1 FA - B-oxidation of FA occurs in most tissues except brain and RBC.
o FA oxidation cannot guarantee rapid enough ATP production in neurons of brain
o No mitochondria in RBC
What is lipogenesis?
Lipid Synthesis: Lipogenesis
- Process by which glucose is converted to FA to form fat.
What two steps are involved in the process of lipogenesis?
- Essentially a 2 step process:
1. Glucose -> pyruvate -> TCA cycle -> citrate leaves cycle and mitochondrion
2. Citrate in cytosol broken down by ATP-citrate lyase (ACLY) -> acetyl Co-A + HCO3 - + ATP (acetyl CoA carboxylase: ACCA) -> Malonyl CoA (2 carbon elongator) -> FA
What determines the extension of the FA during lipogenesis?
Where does lipogenesis occur?
- The formation of malonyl CoA determines the extension of the FA since each malonyl CoA formed is added to growing FA chain using enzyme fatty acid synthase.
- Occurs mostly in liver, white adipose tissue and lactating mammary glands.
- Essential (poly unsaturated) vs non-essential FA?
How is lipogenesis regulated?
- Main regulating step of lipogenesis is the conversion of acetyl CoA malonyl CoA controlled by the enzyme:
o acetyl CoA carboxylase (ACC) - Malonyl Co-A acts as an allosteric inhibitor of the Carnitine shuttle.
- ACC is regulated in 3 ways:
- Polymerization which occurs in the presence of citrate, depolymerization by palmitoyl CoA
- Phosphorylation by cAMP-dependent kinases renders it inactive (glucagon) but insulin opposes phosphorylation and makes it active.
- Gene/protein expression level (long term)
What are ketone bodies? How are they different to fatty acids? Which organs can they be used by? Where are they synthesised?
- Name given to 3 molecules produced during the break down of FA
- Only difference is that they are water-soluble so easier to transport.
- Can be used by a number of organs (including brain) to generate energy
- Synthesized ONLY in the liver from acetyl CoA during ketogenesis
Which ketone bodies can be formed from acetyl CoA during ketogenesis? Which steps then follow this? What stimulates this process?
- Ketone bodies (acetoacetate and hydroxybutyrate) are produced from 3 acetyl CoA that join to form hydroxy-methyl-glutaryl-CoA.
- HMG-CoA is then broken down to acetoacetate which can be converted to beta-hydroxybutyric acid or acetone.
- Main limiting/regulatory step is the formation of HMG-CoA by HMG-CoA synthase
- Synthesis of HMG-CoA synthase is stimulated by fasting, dietary fat, glucagon or insulin deficiency
How and where can ketone bodies be used as energy?
- Ketone bodies are used by many tissues (except liver) as a source of acetyl CoA which can be shuttled immediately into the TCA cycle.
o Mostly used by brain and muscle under starvation; new born babies.
What is a serious condition caused by ketone bodies?
- A serious complication of diabetes is called ketoacidosis:
o Untreated diabetes causes excessive high levels of ketone bodies which when released into the blood decrease the pH of the blood leading to an increase in acidity (acidosis).
o Insulin inhibits important enzymes that stop ketogenesis: this is lost in diabetes
o Acetoacetate and 3-hydroxybutyrate spontaneously form acetone when in excess – acetone breath
What is ketoacidosis? What are its symptoms, triggers and treatment?
- Leading cause of death in people under 24 with diabetes
- Symptoms: bad breath (acetone), extreme thirst & urination, nausea, vomiting, lethargy, confusion, hyperventilation.
- Triggers: low carb diet (body switches to lipolysis and ketogenesis for energy); missing a dose of insulin; infections, stress; alcohol; some medications; acute illness (anything that effects the body’s ability to use or produce insulin)
- Treatment: IV fluids, replacement of electrolytes, IV insulin
What can acetyl Co-A be produced from?
- Acetyl Co-A can be produced from: o Glucose o Fatty acids (B-oxidation) o Ketone bodies o Some amino acids
What can Acetyl Co-A be transferred to?
- Acetyl Co-A can be transferred to:
o Fatty acids
o Ketone bodies
o TCA cycle
What is end-product regulation of acetyl Co-A?
o Various pathways exist to prevent the over –production of acetyl Co-A
What is metabolic flexibility? How can it be improved? What is metabolic inflexibility, when does it occur and what does it cause?
- The ability to switch from glucose to fats as a source of energy as a response to the changes in metabolic demands (exercise vs fasting)
- People who exercise regularly tend to have good metabolic flexibility
- Metabolic inflexibility tends to occur in obese and diabetic people
o Energy shift is impaired or slowed down resulting in inefficient energy consumption
o Have decreased ability to burn fat
Summarise fat metabolism.
- Triglycerides are an essential source of energy
- Broken down mostly in liver & muscle only in the presence of oxygen.
- Lipolysis (break down of fats) is controlled by hormone-sensitive lipase through cAMP-kinase-phosphorylation and by adipose triglyceride lipase (ATGL) enzyme.
- Fatty acids are then broken down to acetyl Co-A (β-oxidation) in mitochondria and controlled mainly through the Carnitine shuttle (regulation of carnitine palmitoyl transferase I [CPT] enzyme)
- Spiral β-oxidation process generates acetyl Co-A + NADH and FADH2, occurs in most cells except brain + RBC
- Lipogenesis occurs through intermediates such as malonyl Co-A and regulated mainly by enzyme acetyl Co-A carboxylase (ACC) through polymerisation, phosphorylation & gene expression.
- Ketone bodies – important source of energy during exercise and starvation; formed from acetyl CoA and regulated by hydroxymethylglutaryl CoA synthase (HMG-CoA synthase).
- Ketoacidosis – clinically relevant complication of diabetes.
- Metabolic flexibility.
