HOw is energy released from TAGs?
They are hydrolyzed by lipase-- either 1. Lipoprotein lipase- for TAGs in plasma or 2. Hormone-sensitive lipase- intiaites TAG hydrolysis in adipose and release prodcuts to plasma
Where are lipoproteins lipase located? How do they work?
Lipoprotein lipases (hydroylze TAG in plasma lipoproteins)- are on surface of endothelial cells of capillaries.
They hydrolyzes fatty acids from the 1 or 3 position of TAGs or DiAGs present in chylomicrons or VLDL. THe FA from the hydrolysis binds to albumin or is taken up by tissue.
Needs Apoprotein CII for activation and stumulated by insulin
Difference in hydrolysis of TAGs/DiAGs and Monoaclyglycerol
TAGs/DiAGs are hydrolyzed by lipoprotein lipase while monacylglycerol either pass into the cell or are hydrolyzed by serum monoacylglycerol hydrolase.
Enzyme that hydrolyzing TAGs from adipose. How does it work?
TAGs in adipose are hydrolyzed by hormone-senstiive lipaes
Acts on the surface on adipose tissue, so when hormone (glucagon, although Epinephrine can stimulate it too) hits the signal that energy is needed, this lipase is active and can liberate FA from glycerol.
FA bind to albumin and are transported for use
Glycerol goes back to liver and can be used for glycolysis or gluconeogenosis
Explain how hormone senstive lipase are trigger and mechanism
Glucagon or Epi hit the adipocytes, which upregulates cAMP and PKA so phosphorylates the enzyme, activating enzyme which starts to cleave FA from triglycerols
Regulatin of hormone senstive lipase
Upregulate- glucagon, Epipherine
Regulation of Lipoprotein Lipase
The delivery of VLDL and chylomicron must have the CII for notciing
Activated by insulin
What organs/systems use FA more? WHy?
Cardiac and muscle because they have high potential energy
When energy is low they use only FA to save glucose for the brain since FA/long chain fatty acids can't pass into the brain because of the BBB.
How are FA activated? What are the steps for beta oxidation?
By conversion to Fatty Acyl CoA by fatty acylCoA synthase located on the OUTER mitochondrial membrane and this requires 1 ATP
Even after activation CPT 1 helps the FA cross the outer mitochondrial membrane which causing a loss of activation
Then the FA is transferred to Carinitine (bound together) and it carries acyl gorup
This helps carry the FA to the mitochondrial matrix where another ATP is used to reactivate the FA for B-oxidation
Energy from Beta Oxidation
A palmitate has 16 carbons so could make 8AcetylCoA each of ehich could enter the TCA
Also with every turn you have FADH2 and NADH liberated that can go to terminal oxidation
So you get up to 129 ATP-- remember that FA oxidation requires mitochonria and good oxygenation
What's special about small and mediucm FA
They don't need caritine. They still beed activation to reach Beta oxidation!
Four step reactions of Beta oxidation
1. Acyl CoA in the inner mitochondrial membrane (already activated and carried by CPT1, carnitine, and CPT II) is dehydrogenated by one of the 4 acyl CoA Dehydrogenase VLCAD – for very-long chain FAs (C20-24)– works in peroxisomes only
LCAD – for long chain FAs (C12-18)
MCAD – for medium chain FAs (C6-10)
SCAD – for short chain FAs (C4-6)
1. Fatty acyl CoA---- acyl CoA DH--> Enoyl CoA
2. Enoyl--- enoyl COA hydratase---> 3-L hydroxyacyl CoA (hydrolyzing the trans double bond)
3.3-L hydroxyacyl CoA--- 3-L hydroxyacyl CoA DH---> B-ketoacyl-CoA
4. Thiolase cleaves off a two carbon fragment
Dicuss effects of missing a Acyl CoA DH
This is the family of DH that is the first step of beta oxidatoin. If they are missing there is fatty acid in the liver and can cause hepatic mitochondrial damage and impaired liver function.
When There is an accumulation of FA is accumulates then spill sback to the liver. We will see some FA chains bound to the carnitine--- carnitine bound FA is an early indicator that the DH is missing
Regulation of Beta Oxidation
Upregulated by- presense of cofactos and substrates ad the rate of actyl CoA from the TCA cycle
Carnitine from the matrix to the inner mitochondrial is the rate limiting step
Malonyl CoA (first activated unit in FA acid synthesis) inhibits CPT1 (carry FA from the cytosol into the matrix) -- this is only in cells that can produce FA- liver and adipose tissue
Energetics of Beta-Oxidation
Each round makes 1 acrtyl CoA, 1 NADH, 1FADH2
making 8AcCoA + 7 FADH + 7NADH (we only do 7 rounds because the last product comes from a C4 is cleaved into two)
Special pathways- what do we do with odd chain fatty acids?
In degardation we end with a 3 carbon chain (Propionyl CoA)- which can be modified (carboxylated to methylmalonyl CoA and rearranged to Succyl CoA) which can be used for gluconeogenosis
This requires Biotin and B12 to make Succinyl CoA
Special pathways- what do we do with unsaturated fatty acids in degradation?
THe kink is normally in a cis conformation (if it's in trans the enzymes can work on it) so we usean isomerase to switch the cis to trans.
Discuss degradation of polyunsaturated FA
THey have several double bonds and they need extra enzymes that require NADPH (from the PPP)
Explain waht happens to VLC FA
Very long chain FA (over 20) can't enter the mitochondria so they go peroxisomes for Beta oxidation shortening to 16. which intially produces FADH2.
Catalase reduces water - good indicator of where the perioxisomes are.
There is no energy gerneration in the perioxisomes-- its just for modication and removal.
What do perixisomes handle
Branched beta chain oxidation and very long chain beta oxidation
What is lapha oxidation?
Mainly in the ER and mitochondria and hydroxylate fatty acids through the cytochrom P450 system, need NADPH and O2
What are ketone bodies
Water slouble lipid based energy that are mainly acetoacetic acid and produced in the liver (and kidney) within the mitochondrial matrix
Production of ketone bodies
3 acetyl CoA-----> hydroxymethylgltaryl coenzyme A (HMG CoA)
HMG CoA--- HMG CoA lyase---> acetoacetic acid and acetyl CoA
acetoacetic and hydrobutyrate are the two main precursors to the ketone---when in circulation during fasting they can spontaneously produce acetone (often happens in diabetics)
Usage of ketone bodies
They go into circultoin and taken up tissues nad cell that need it minaly the CNS under starvation but muscle cells can also channel ketone bodies to Beta Oxidation
Fate of AcCoA in the liver
If in the mitochondria we can use it to in TCA for energy (and in liver for ketone synthesis)
When under insulin we would acetyl CoA will be used for Choelsterol and FA synthesis