Lipid Metabolism - Lecture 8

lipids are soluble in _________ solvents such as _____ and _____

organic, chloroform, methanol

explain the structure of fatty acids

carboxylic acids with long chain hydrocarbon side groups
usually occur in esterified form as components of the various lipids
the hydrocarbon chains are usually C16 or C18
fatty acid double bonds almost always have the cis configuration

fatty acid double bonds are almost always in the cis/trans configuration

cis

explain the differences between unsaturated and saturated fatty acids

unsaturated → contain double bonds (usually cis)
saturated → no double bonds

unsaturated fatty acids have a kink in their hydrocarbon chain at the site of the double bond, which means they cannot pack together as tightly as their saturated counterparts
it also reduces their van der waal interactions, leading to a decrease in their melting point (liquid at room temp) with the degree of unsaturation
the fluidity also increases with the degree of unsaturation

what is a triaglycerol

a fatty acid ester of glycerol → 3 fatty acid chains bound to the 3 OH groups of glycerol
function as energy sources in plants and animals (also their most abundant form of lipids, even though they are not components of the cell membranes)

________ are the most abundant form of lipids in plants and animals

triaglycerols

explain why triaglycerols are such a good energy storage molecule

triaglycerols are less oxidized than carbs or proteins and therefore yield more energy per unit mass on complete oxidation

glycogen also binds about twice its weight in water, whereas since traiglycerols are non-polar they do not bind any water and therefore provide about 6x the amount of energy as an equal weight of glycogen

explain the function of adipocytes

responsible for the release (under hormonal control) and storage of triaglycerols

their cytosol is almost entirely filled with fat globules

it provides long-term energy storage and thermal insulation

adipose tissue is most abundant in the ________ layer and in the ________ ______

subcutaneous, abdominal cavity

what is the function of acetyl-CoA

involved in protein, carbohydrate and lipid metabolism
main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production

triaglycerols make up __% of dietary lipids

90

explain the determining factor of the rate of lipid metabolism

since lipid metabolism enzymes are water soluble and lipids are water insoluble, the breakdown of the lipids must occur at lipid-water interfaces, meaning that the rate of lipid breakdown depends on the surface area of the lipid exposed to the water soluble region

→ the surface area is increased by

1. the peristaltic movement of the intestine

2. emulsifying properties of bile salts

explain the function of bile salts in lipid metabolism

Tri-acylglycerols (fat) molecules are highly hydrophobic. After ingestion they are present in the form of oil droplets. In order to get digested and absorbed, they need to be emulsified (partially solubilized) by bile salts

they are detergent-like, amphipathic molecules that solubilize fat globules by breaking them down into smaller fat droplets (increases the lipid-water interface surface area)

• the micelles of triaglycerol and bile salts combines with cholesterol and phosphatidyl choline, forming soluble mixed micelles

what is the structure of bile salts

they are cholesterol derivatives synthesized by the liver and deposited in the gall bladder for storage as glycine or taurine conjugates, where they are then released into the small intestine

• they are amphipathic molecules that can interact with both the fat droplets made of triaglycerols and water

what is the function of pancreatic lipases in lipid metabolism

pancreatic lipases catalyze the hydrolysis of triaglycerols at the C1 and C3 positions to form 1,2-diaglycerols and 2-acylglycerols, with the help of Na+ and K+ in the intestine

• the fatty acids are more still not completely soluble so they begin to form mixed micelles with phosphatidyl choline, bile salts and cholesterol

• its enzyme activity increases at lipid-water interface (interfacial activation)
  binding to the water-lipid interface requires mixed micelles of phospnatidyl choline and bile salts and colipase which forms a complex with lipase

what are lipoproteins

complexes of lipids and protein
globular, micelle-like particles

triaglycerol and cholesteryl esters surrounded by an amphiphilic coat of protein, phospholipids and cholesterol

five classes: chylomicrons (exogenous pathway → externally ingested triaglycerols), VLDL, IDL, LDL and HDL (all part of the endogenous pathway → internally produced triaglycerols)

HDL is the most ____ of the lipoproteins

dense

explain the transport of triaglycerols and cholesterol

1. chylomicrons adhere to binding sites on the inner surface of the capillaries in skeletal muscle and adipose tissue

2. lipoprotein lipase hydrolyzes the triaglycerols on the chylomicron, allowing for the tissues to take up monoacylglycerol and fatty acids

3. as the chylomicrons are depleted of triaglycerols, they become cholesterol enriched chylomicron remnants

4. the remnants dissociate from the capillary and re-enter circulation to be taken up by the liver
   overall: chylomicrons deliver dietary triaglycerols to muscle and adipose tissue, and dietary cholesterol to the liver

what happens to the fatty acids in the muscle (fatty acid oxidation)

1. fatty acid activation (before oxidation): fatty acyl CoA synthase convert fatty acids to fatty acyl CoA (makes them more desperate to react) → coupled to ATP hydrolysis

2. fatty acyl CoA needs to be transported into the mitochondria, where beta oxidation occurs, via a carnitine transporter

3. each round of mitochondrial B oxidation produces FADH2, NADH and acetyl CoA, removing two carbons from the fatty acid in each cycle

4. additional enzymes are required to oxidize unsaturated fats

odd chain fatty acid → _______ _____ (breakdown product) → _______ _____ (excretion product)

benzoic acid, hippuric acid

even chain fatty acid → ______ ____ (breakdown product) → _____ ___ (excretion product)

phenylacetic acid, phenylaceturic acid

what is the function of the acyl-CoA synthetase mechanism

they prime the fatty acids, which is necessary for them to undergo oxidation
ATP-dependent acylation reaction to form fatty acyl CoA

at least three acyl-CoA synthetases (thiokinases) exist, which differ in their chain length specificities

these enzymes are associated with either the endoplasmic reticulum or the mitochondria and all catalyze this reaction

fatty acid + ATP → fatty acyl-COA + AMP + PPi

explain the carnitine shuttle in the mitochondrial membrane

a long fatty acyl-CoA chain cannot cross the inner mitochondrial membrane

1. the acyl group is transferred to a carnitine molecule in the cytosol (acyl-carnitine), by carnitine palmitoyl transferase 1, which can then move across the mitochondrial membrane through the carnitine carrier protein

2. inside the mitochondria, another enzyme called carnitine palmitoyl transferase II reverses the reaction, regenerating acyl CoA which can now undergo B oxidation

explain the 4 reactions of B oxidation of fatty acyl-CoA

1. Dehydrogenation to Form a Double Bond:

   • Enzyme: Acyl-CoA dehydrogenase (AD).

   • What Happens: AD removes two hydrogen atoms from the fatty acyl-CoA, creating a trans-α,β double bond between the α and β carbon atoms. This step changes the structure of the molecule, setting the stage for the next steps.

   • Result: Formation of a molecule with a double bond, ready for the next reaction.

2. Hydration of the Double Bond:

   • Enzyme: Enoyl-CoA hydratase (EH).

   • What Happens: EH adds a water molecule across the double bond that was created in the first step. This means one part of the water (the hydrogen, H) attaches to one side of the bond, and the other part (the hydroxyl group, OH) attaches to the other side.

   • Result: A molecule called 3-L-hydroxyacyl-CoA, which has an OH group added to it, making it ready for further modification.

3. Dehydrogenation to Form a Keto Group:

   • Enzyme: 3-L-hydroxyacyl-CoA dehydrogenase (HAD).

   • What Happens: HAD removes two more hydrogen atoms, this time from the molecule formed in step 2. This action converts the hydroxyl group (OH) into a keto group (=O) at the β position.

   • Result: Formation of β-ketoacyl-CoA, which has a keto group ready for the final reaction.

4. Thiolysis, Cutting the Chain:

   • Enzyme: β-ketoacyl-CoA thiolase (KT), also simply called thiolase.

   • What Happens: KT breaks the β-ketoacyl-CoA molecule by adding another CoA molecule. This cut happens between the α and β carbon atoms, releasing a molecule of acetyl-CoA (which can enter the citric acid cycle for energy production) and leaving behind a shorter acyl-CoA molecule.

   • Result: This shorter acyl-CoA is now two carbon atoms less than it was originally. It can enter the β-oxidation cycle again to be broken down further, releasing more acetyl-CoA each time through the cycle.

what are the substrates and enzymes of fatty acid B oxidation

1. Acyl-CoA dehydrogenase: fatty acyl CoA → enoyl CoA, using FAD as oxidizing agent

2. Enoyl-CoA hydratase:

   enoyl CoA + H2O → 3-hydroxyacyl-CoA

3. 3-hydroxyacyl-CoA dehydrogenase: 3-hydroxyacyl-CoA → B-ketoacyl-CoA, using NAD+ as reducing agent (generates NADH)

4. β-ketoacyl-CoA thiolase:

   B-ketoacyl-CoA + CoA → fatty acyl CoA + acetyl CoA