17. Fat Metabolism Flashcards
What is used for a long-term energy store?
How is fat stored?
What are the fates of the breakdown products of lipids?
What regulates lipolysis (fat release from adipose tissue)?
Lipids (triacyl glycerol) and ketone bodies. Body has almost limitless ability to store them (unlike glycogen).
As adipose tissue in globules in cytoplasm (white adipose in particular)
FAs: beta-oxidised for energy (in oxidative tissues e.g. muscle/liver) or converted to ketone bodies (liver) for use in non-oxidative tissues. Glycerol: used for glucose synthesis (liver) (or gluconeogenesis to maintain BG)
Control at level of hydrolysis enzyme HSL - sensitive to cAMP levels which respond to hormonal signals. (Glucose levels high: body doesn’t break down fat and insulin = HSL levels blocked; glucagon high/adrenaline = enzymes phosphorylated = activates HSL -> break down fat) HSL = hormone-sensitive lipase
Is hormone sensitive lipolysis completely dependant on HSL?
Briefly describe the oxidation of fatty acids.
No - adipose triglyceride lipase (ATGL): produces diacylglycerol for HSL to work on. ATGL expression level relates to nutritional status. Also a small bit found in other tissues e.g heart. So need combo of HSL and ATGL to break down fat.
3 steps: 1) activation of FA by acetyl CoA. 2) Transport into mitochondria via carnitine shuttle. 3) Beta-oxidation
Describe beta oxidation.
Why are different isoforms of enzymes present?
What are the products?
Can unsaturated fats feed into this pathway?
Cyclic (spiral) process which remove 2C units from the long fat chain each time: goes around in circle with chain getting progressivly shorter until have only 2C units left. Involves 2 dehydrogenases, and H2O and CoA addition.
Have different chain length preferences - work on diff lengths of fat chain e.g. acetyl CoA dehydrogenase likes long-medium chains.
Lots of ACoA and reduced FAD and NAD (feed into aerobic resp).
Yes but require extra enzymes
Describe how fat enters the mitochondria.
Are the enzymes controlled in this process (like glycolysis)?
Multistep process: carnitine shuffle.
1) In cytosol ATP used to add CoA onto FA
2) Fatty acyl CoA interacts with CPT1 -> transports it across outer mitochondrial membrane to inner membrane space and adds it to carnitine, losing CoA
3) Fatty acyl-carnitine transported to mitochondrial matrix via translocase and CPT2 takes FA off carnitine and attaches CoA back to FA instead. Carnitine ‘shuffles’ back. Then beta oxidation can occur.
No - this control is down to transport - once a fat in mitochondria = gone
The main point of fatty acid catabolism control is transport. What 3 things regulate this?
1) Inhibited by malonyl-CoA which is involved in fatty acid synthesis (imp b/c is involved in fat synthesis, so prevents fats being made and broken down in same cell)
2) Stimulated by glucagon via cAMP (so when low BG, encourages body to switch to fat)
3) Regulated transcriptionally with levels rising in extended fasting/diabetes (e.g. increases transcription)
Where does fatty acid not occur?
Recap: how many ATP are lost when fatty acids are activated?
Why can’t fat be used for gluconeogenesis?
Brain (dependant on glucose for energy). And tissues that don’t have mitochondria e.g. RBC.
2
When go round TCA - lose 2C equivalent to the 2C putting in as Acetyl CoA from FA. But energy can be used to drive it, just not the C.
Describe the 2 stages of lipogenesis.
Where does this happen?
Why does fat synthesis not occur at the same time as breakdown?
1) Formation of malonyl CoA: Glucose -> pyruvate -> into mitochondria -> acetyl CoA -> citrate -> into cytosol -> acetyl CoA -> malonyl CoA
2) FA synthetase: malonyl CoA enters cyclic process that creates fatty acid chains (almost revese process to beta oxidation!)
Liver, white adipose tissue, lactating mammary glands
Malonyl CoA is high when glucose levels are high and inhibits CPT1 so no carnitine shuffle, so fat not broken down at same time.
What is the main regulatory step in lipid synthesis?
What are the 3 ways in which this regulatory step is controlled?
Acetyl-CoA carboxylase: it converts acetyl CoA to malonyl CoA, which inhibits carnitine shuffle and thus fatty acid oxidation.
The enzyme is controlled by:
1) polymerisation: promoted by citrate (provides substrate), inhibited by palmitoyl CoA (a fatty acid). Monomer = inactive. Polymer = active.
2) phosphorylation by AMP-dependant kinase and PKA, controlled by insulin (if high, produce malonyl CoA -> favours fat synthesis) and glucagon (activates cAMP -> activates PKA -> phosphorylates Acetyl-CoA carboxylase = inactive. Thus no malonyl CoA produced - favours fat breakdown).
3) longer tem genetic control e.g. if starved alot, will have little of this enzyme.
What are ketone bodies?
What are they produced from, and where?
Name 2 ketone bodies
Soluble fuels which can be used in the place of glucose by a number of tissues. Liver oxidieses fat to KB and sends it to tissues where it can be converted back to acetyl-CoA and fed into TCA.
Produced from acetyl-CoA, only in the liver in the mitochondria
Acetoacetate and beta-hydroxybutyrate
How are ketone bodies made e.g. acetoacetate?
What can acetoacetate be reduced to?
What happens to the ketone bodies in target tissues?
How is HMG-CoA synthase regulated?
Fusion of acetyl-CoA moelecules. To make acetoacetate: 2 acetyl CoA combine = acetoacetyl coA -> combine with a third acetyl CoA via HMG CoA synthase -> product modulated by HMG CoA lyase -> acetoacetate.
Beta-hydroxybutyrate
Acetoacetate/beta-hydroxybutyrate converted to acetyl CoA -> TCA -> energy
Via transcription - so if prolong starvation -> make more of it. It’s also covalently modified by acetylation (active - deacetylation)
How are ketone bodies utilised?
What does the brain switch to using for fuel during starvation? (Give %)
Can the liver oxidise ketone bodies?
Describe the body’s fuel sources as the hours increse from the time someoe last ate a meal.
By extrahepatic tissues -> converted bak to ACoA and used for TCA.
Switch from 100% glucose -> 50% from ketone bodies. Also used in heart and skeletal muscle. Imp fuel in babies
No.
Short-tem (1-4hrs): use mainly glucose from that meal. 4-12hrs: switich to using glycogen. (Liver glycogen takes over producing BG). About 16hrs: Glycogen depleted - liver gluconeogenesis takes over. Multiple days: switch to ketones to avoid breaking down proteins (AA -> fuel) = survive longer.
What inhibits ketone body production?
How does diabetes fare with ketone bodies?
Why can ketone bodies cause problems?
Insulin.
Can be excessive ketone body production - no insulin signalling so lose control and lots of fat released in blood -> transported to mitochondria and liver -> produce lots of ACoA. Since body doesn’t really need energy it’s shunted to ketone body production -> lots of KB produced.
Acidic. If produce lots in blood -> ketoacidosis.
What controls
a) fat metabolism?
b) glucose metabolism?
What do high levels of NADH inhibit?
Why, when PDC is active, do we metabolise glucose instead of fat (i.e what stops fat metabolism)?
a) Carnitine shufle
b) Pyruvate dehydrogenase complex (controlled by insulin and glucagon: glucose high = promotes glycolysis and PDC, and when low, inhibits it)
* So by controlling these two, can change balance between glucose and fat metabolism.*
PDC. Beta oxidation of fats produces lots of NADH so it inhibis PDC.
When PDC active, uses glucose -> TCA so prod lots of citrate -> converted to ACoA in cytosol -> malonyl CoA -> controls carnitine shuffle (high mal CoA inhibits it) - in time a plently we metabolise and use glucose instead of fat.
What controls PDC at the end of glycolysis?
What is metabolic flexibility?
Is this the same for all individuals?
What is metabolic inflexibility?
Feedback inhibition and covalent modification via phosphorylation by PDH kinase and PKA
Ability to switch between using glucose/lipids
No - sedentary: small range of switching between the 2 compared to fit people.
Inability to switch between fasting and insulin stimulation
