How do bile salts function in digestion?
bile salts reduce surface tension and break fat globules into droplets. this is called emulsification; results in lipid micelles
What does lipid digestion break triacylglycerols into?
Fatty acids, mono- and diacylglycerols
What occurs in intestinal cells after fatty acids are absorbed?
They form complexes with intestinal fatty acid binding protein (I-FABP)
How are lipids transported in the blood?
as lipoproteins
What are the components of lipoproteins?
Membrane:
- Apolipoproteins
- Cholesterol
- Phospholipids
Core:
- Cholesteryl esters
- Triacylglycerols
What are the different types of lipoproteins and their functions?
-chylomicrons: are synthesized in the intestinal cells; transport TAGs absorbed from the intestines to various tissues
-VLDL, IDL, and LDLs are synthesized in the liver to transport endogenous TAGs and cholesterol from the liver to the tissues
-HDL: trans
How do cells take up LDL?
Receptor-mediated endocytosis. LDL particles are sequestered by LDL receptors and the LDL receptors cluster into clathrin-coated pits which gather the cell surface receptors that are destined for endocytosis. The coated pits invaginate from the plasma mem
How are fatty acids activated? Where does this occur?
By turning them into fatty acyl-CoA which is catalyzed by acyl-CoA synthetase. This occurs in the cytosol
Where does beta oxidation occur?
mitochondrial matrix
How are fatty acids transported into the mitochondria?
1. Carnitine palmitoyl transferase I transfers an acyl group to carnitine.
2. Acyl-carnitine transported by acyl-carnitine transporter protein
3. Acyl group transferred back to CoASH by carnitine palmitoyl transferase II
What kind of fatty acids can diffuse freely across the membrane?
Small ones (<12 carbons)
What are the 3 stages of fatty acid oxidation?
1. beta-oxidation of FA chain to produce acetyl-CoA units
2. Oxidation of acetyl-CoA into CO2 via the TCA cycle
3. ATP generation from NADH and FADH2 via the ETC
What are the 4 steps of beta oxidation?
1. oxidation
2. hydration
3. oxidation
4. thiolysis (cleavage)
What does step one of beta oxidation involve?
The dehydrogenation of an alkane to an alkene which results in a trans double bond. The enzyme is acyl-CoA dehydrogenase and requires FAD as a cofactor
What does step two of beta oxidation involve?
The hydration of the alkene. Enoyl-CoA hydratase adds water across a double bond yielding alcohol.
What does step three of beta oxidation involve?
The dehydrogenation of the alcohol. The enzyme is beta-hydroxyacyl-CoA dehydrogenase and it requires NAD+ as a cofactor. Only L isomers of hydroxy acyl CoA act as substrates
What does step four of beta oxidation involve?
The transfer of the fatty acid chain. The enzyme is beta-ketoacyl-CoA thiolase and the active site thiolate acts as a nucleophile and releases acetyl-CoA from the chain. The terminal sulfur in CoASH then acts a nucleophile and picks up the fatty acid chai
What two additional enzymes are required for the oxidation of unsaturated fatty acids?
1. Enoyl-CoA isomerase: converts cis double bonds starting at C3 to trans double bonds
2. Dienoyl-CoA reductase: reduces cis bonds not at C3
What additional enzymes do monounsaturated fatty acids require?
The isomerase
What additional enzymes do polyunsaturated fatty acids require?
Both the isomerase and the reductase
What does the oxidation of odd numbered fatty acids produce?
In the last step acetyl-CoA and propionyl-CoA are formed
What happens to the propionyl-CoA produced in beta oxidation of odd numbered fatty acids? How does this product enter the TCA cycle?
it is converted in succinyl-CoA. It is converted to malate which is transported to the cytosol and converted to pyruvate (via malic enzyme) and then reimported to the mitochondria and converted to acetyl-CoA
What cofactor does the conversion of propionyl-CoA to succinyl-CoA require?
Vitamin B12
How does mitochondrial acyl-CoA dehydrogenase pass electrons to the ETC?
Via electron-transferring flavoprotein (ETF)
What does peroxisomal/glyoxysomal acy-CoA dehydrogenase pass electrons to?
It passes electrons directly to molecular oxygen which produces H2O2 but not ATP; energy is released as heat
How is they hydrogen peroxide produced in peroxisomes eliminated?
By catalase
What happens to acetyl-CoA when oxaloacetate is depleted?
It is converted into ketone bodies which frees coenzyme A for continued beta oxidation
How are ketone bodies formed?
1. Thiolase joins 2 acetyl-CoAs to form acetoacetyl-CoA
2. Acetoacetyl-CoA is converted to beta-hydroxy-beta-methylglutaryl-CoA by HMG-CoA synthase
3. HMG is split it acetyl-CoA (can become acetone) and acetoacetate which can be reduced to D-beta-hydroxyb
Can ketone bodies be converted back to acetyl-CoA?
Yass
What organ produces ketone bodies?
liver
What is the function of ketone bodies?
They can serve as fuels for organs other than the liver - the brain can use ketone bodies instead of glucose during starvation
What is the danger of excess ketone bodies production?
It can lower the blood pH dangerously (acidosis)
Where does fatty acid synthesis occur?
cytosol
How is malonyl CoA synthesized?
Acetyl-CoA carboxylase adds a CO2 (bicarbonate) to acetyl-CoA; ACC uses biotin as a cofactor (carries the CO2)
Compare catabolism and anabolism of fatty acids:
Catabolism:
-produces acetyl-CoA
-produces reducing power (NADH)
-takes place in the mitochondria
Anabolism:
-requires acetyl-CoA and malonyl-CoA
-requires reducing power from NADPH
-takes place in the cytosol in animals and chloroplasts in plants
What are the 4 steps of fatty acid synthesis?
1. Condensation reaction: forms a new C-C bond
2. Reduction of bond
3. Dehydration of bond
4. Reduction of bond
Repeat 7-8 times
What is the priming step of fatty acid synthesis?
Acetyl-CoA is converted to acetyl-ACP and malonyl-CoA is converted to malonyl-ACP (catalyzed by malonyl-acetyl-CoA-ACP transacylase)
What is acyl carrier protein?
It anchors the growing FA and delivers acetate/malonate to the FAS and shuttles the growing chain from one active site to another during the 4 step reaction; it has a flexible arm that serves to tether acyl chain while carrying intermediates from one enzy
What is the enzyme involved in fatty acid synthesis?
Fatty acid synthase (FAS)
How does acetyl-CoA enter the cytosol to take place in fatty acid synthesis?
1. Acetyl-CoA is converted to citrate by citrate synthase
2. Citrate passes through the citrate transporter
3. The cytosolic citrate is cleaved by citrate lyase into acetyl-CoA and oxaloacetate
4. Acetyl-CoA can now be used in lipid synthesis
5. Malate DH
What is the product of fatty acid synthesis?
The 16C saturated FA palmitate
What drives beta-ketoacyl-ACP synthase?
The decarboxylation of malonyl-ACP
What happens in step 1 of FA synthesis? (the step after the priming step)
Malonoyl-ACP is decarboxylated and attached to acetyl-ACP (catalzyed by beta-ketoacyl synthase)
What happens in step 2 of FA synthesis?
The carbonyl is reduced - requires NADPH
What happens in step 3 of FA synthesis?
The alcohol is dehydrated
What happens in step 4 of FA synthesis?
The trans double bond is reduced - requires NADPH
How can Palmitate be modified
It can be elongated in the ER or mitochondria and/or it can be desaturated
What is fatty acyl-CoA desaturase?
Enzyme that desaturates palmitate; requires NADPH
What desaturases do humans have?
Delta 4,5,6 and 9; cannot desaturate beyond delta 9
What are the essential fatty acids?
linoleic acid and linolenic acid; humans cannot produce these
What are polyunsaturated fatty acids?
Fatty acids that help to control membrane fluidity and are also precursors to eicosanoids (signalling molecules)
What is the precursor for the backbone of fat and phospholipids?
glycerol-3-phosphate
How is glycerol-3-phosphate produced?
From siphoning DHAP from glycolysis and converting it via glycerol-3-phosphate dehydrogenase
What is an alternative way to make glycerol-3-phosphate instead of using DHAP?
From glycerol using glycerol kinase (this is a minor pathway in the liver and kidneys)
How are triacylglycerols formed?
They are synthesized from fatty acyl-CoA esters and glycerol-3-phosphate or DHAP. Acyl transferase can convert gly-3-P to lysophosphatidic acid which can be converted to phosphatidic acid (via another acyl transferase) which can then be dephosphorylated a
How are phospholipids formed?
Phosphatidic acid or DAGs can be used to produce phospholipids
What are the activators and inhibitors of ACC?
Activators: Citrate, insulin
Inhibitors: Palmitate, AMP
How is malonyl-CoA involved in regulation?
Malonyl-CoA inhibits carnitine palmitoyl transferase I which prevents fatty acids from entering the mitochondria to be oxidized
How is glycolysis inhibited during fatty acid synthesis?
Excess citrate activates ACC (indicates excess acetyl-CoA=excess energy) and inhibits PFK-1 which reduces glycolytic flux to avoid excess fat production
How do glucagon and epinephrine participate in ACC regulation?
They reduce the sensitivity of citrate activation which leads to the phosphorylation and inactivation of ACC
How is FA synthesis regulated in plants and bacteria?
Plant ACC is activated by increases in [Mg2+] and pH (during light reactions)
What is a slower method of regulating FA synthesis?
Changes in gene expression - FAs bind to transcription factors called peroxisome proliferator-activated receptors
How are sphingolipids synthesized?
In the synthesis of sphingolipids, serine and palmityl CoA condense, forming a compound that is related to sphingosine. Reduction of this compound, followed by addition of a second fatty acid in amide linkage, produces ceramide. Carbohydrate groups attach
What are eicosanoids?
biologically active lipids with local hormone-like activity. Includes prostaglandins, leukotrienes, and thromboxanes
What are eicosanoids derived from?
arachidonic acid (20-carbon polyunsaturated fatty acid)
How is arachidonic acid formed?
Phospholipase A2 acting on cell membrane phospholipids - attacks the C2 fatty acid which releases arachidonate
How are prostaglandins produced?
by action of COX1&2 on arachidonic acid
What is another name for prostaglandin H2 synthase?
COX
How does COX alter arachidonate?
1. Its cyclooxygenase activity adds 2O2 to arachidonate to form PGG2
2. Its peroxidase activity converts PGG2 to PGH2
PGH2 is a precursor to other eicosanoids
What are some inhibitors of COX?
Aspirin, ibuprofen, and acetaminophen
How does aspirin inhibit COX?
Aspirin irreversibly inhibits COX-1 and COX-2, via acetylation of serine in active site of enzyme
How do ibuprofen and acetaminophen inhibit COX?
They are reversible competitive inhibitors. Ibuprofen binds COX-1 and COX-2 and acetaminophen binds COX-3
How is cholesterol synthesis regulated?
By HMG-CoA reductase (catalyzes the rate-determining step)
What are the 4 steps of cholesterol synthesis?
1. 3 acetate condense to form mevalonate (key compound) via HMG-CoA intermediate
2. Mevalonate converts to phosphorylated 5C isoprene
3. 6 isoprenes polymerize to form the 30C linear squalene
4. Squalene cyclizes to form the 4 rings that are modified to p
What is cholesterol-mediated sterol regulatory element-bind protein?
When cholesterol levels are low, SREBP is activated which results in the production of more HMG-CoA reductase
How does a normal cell inport and export cholesterol?
LDL receptor brings in whole LDL molecule by endocytosis, packages cholesterol which then gets transported out in HDL through ABCA1 transporter
What is familial hypercholesterolemia?
Genetic disease where � or all of your LDL receptors are dysfunctional; can't bring cholesterol into cells -> high blood levels of cholesterol
What is Tangier disease?
Lack of cholesterol transporter (ABCA1). Cholesterol builds up in macrophages which become foam-like cells)