Lectures 7/8: Fatty Acid Catabolim

Fatty acids are oxidized to what?

• acetyl-Coa

Fatty acid oxidation provides what to the ETC and the citric acid cycle?

• electrons for ETC

• acetyl-Coa for citric acid cylce

What proportion of energy in mammalian heart and liver is from fatty acid oxidation?

• over 80%

What is another name for fatty acid oxidation?

• beta-oxidation

Fatty acids carry long poly-hydrocarbon chains and are therefore more what than carbohydrates?

• more highly reduced

• yields more energy

Fatty acids are very closely packed meaning what?

• carry less water

• non-polar

Glucose and glycogen are for fast usage and short term storage, what makes fatty acids different?

• long term energy

• months at a time

Fatty acids are derived from 3 major sources including…?

• diet

• fats in cells i.e., adipocytes

• fat synthesis

Fatty acids are what?

• monomers of fats

What is the structure of a fatty acid?

• carboxylic acid head → hydrophillic

• hydrocarbon chain → hydrophobic

• amphiphillic

Fatty acids can be what or what?

• saturated

• unsaturated

Saturated fatty acid

• no double bonds

• filled with max number of hydrogens

• straight

Unsaturated fatty acid

• double bonds

• not max number of hydrogens

• kinked

Orientation of the chain around the carbon double bond in an unsaturated fatty acid chain determines what?

• whether it’s cis or trans conformation

Triacylglycerols are responsible for what form of fatty acids?

• polymeric

• storage form

What do the polymeric and storage forms of triacyglycerols involve chemically?

• esterification of 3 fatty acid chains to a single glycerol

Most fatty acids in nature are found in what form and broken down into what?

• triacylglycerol form

• broken down into fatty acids

• when needed for ATP synthesis

What enzyme is responsible for the breakdown of triacyglycerols into fatty acid and glycerol

• lipases

Absorption of dietary fats by intestinal walls begins with what being converted into what?

• fat particles → micelles → fatty acids and glycerol

Bile salts

• emulsify dietary fats in small intestine forming mixed micelles

• bile salts and fatty acids

Bile salts are produced from what and are stored where?

• cholesterol in the liver

• gallbladder and released in small intestine

What is another name for bile salts?

• taurocholic acid

Micelles increase what to the intestinal lipases?

• lipid access

Lipases breakdown triacylglycerols to what?

• monoglycerides

• diglycerides

• free fatty acids

• glycerol

Where are the products of fatty acid breakdown via lipases taken up and what happens afterward?

• intestinal mucosa

• reconverted to triacylglycerols

Triacylglycerols are then packaged into what?

• chylomicrons

What is the structure of a chylomicron?

• cholesterol and lipid-binding proteins (lipoproteins)

Apolipoproteins

• lipid-binding proteins

• transport of triacylglycerols, phospholipids, cholesterol between organs

Lipoproteins form what when combined with hydrophobic particles?

• spherical aggregates

• hydrophobic particles facing inward

• hydrophilic exposed at surface

Surface of chylomicrons is composed of phospholipids and triacylglycerols pointing where?

• inside

Apolipoproteins on the surface of the chylomicron signal what?

• uptake and metabolism of the chylomicrons

Lipids are transported in the blood via…?

• chylomicrons

Chylomicrons are synthesized where and do what?

• intestinal mucosa

• transport triacylglycerols through the blood to tissue

Combination of lipids and proteins creates what?

• different densities of particles

• can be differentiated

VLDL

• made in liver

• deliver liver-synthesized triacylglycerols to adipose tissue

LDL

• major cholesterol carrier (BAD ONE)

• liver to tissue

HDL

• highest protein content

• picks up cholesterol

• moves it from tissue → liver (GOOD ONE)

Packaged chylomicrons are transported from the intestinal mucosa to the what and enters what?

• lymphatic system

• bloodstream

Once in the blood, chylomicrons do what?

• deliver package to muscle and adipose tissues

Lipoprotein lipase

• hyrolyzes triacylglycerols to fatty acids and glycerol

In muscle, fatty acids are oxidized for energy whereas in adipose tissue they are what?

• stored as triacylglycerols

Lipids are stored in adipocytes in what form?

• lipid droplets

What does the centre of lipid droplets contain?

• sterol esters

• triacylglycerols

What doe the surface of the lipid droplets carry?

• perilipins

• phospholipids

Perilipins

• protein

• restricts access to lipid droplets until needed

Hormones signal when metabolic energy is needed and when triacylglycerols should be what?

• released from the lipid droplet

Which hormones are released when blood glucose is low?

• epinephrine

• glucagon

Signal from epinephrine and glucagon results in what?

• activation of adenylyl cyclase in adipocytes

What does the activation of adenylyl cyclase produce?

• cyclic AMP (cAMP)

What does the production of cyclic AMP do?

• activates protein kinase A

Activation of PKA (protein kinase A) results in what?

• phosphorylation of hormone sensitive lipases

  • HSL

• phosphorylation of perilipins found on lipid droplet surface

Phosphorylated perilipins signals lipases to do what?

• release triacylglycerols to free fatty acids and glycerols

Phosphorylated perilipins on lipid droplet surface release what?

• protein CGI

• comparative genetic identification

CGI associates with what?

• ATGL

• adipose triacylglycerol lipase

Activated ATGL hydrolyzes what to a what?

• TAG (triacylglycerol) → DAG (diacylglycerol)

Phophorylated perilipin associates with what allowing for what to access the lipid droplet?

• phosphorylated HSL (hormone sensitive lipase)

HSL hydrolyzes what to whay?

• DAG → MAG (monoacylglycerol)

Monoacylglycerol lipase (MGL) hydrolyzes what to what?

• MAG (monoacylglycerol) → glycerol and free fatty acid

Fatty acids leave adipocyte and are transported via what?

• bloodstream

• bind serum albumin

Fatty acids are then released from serum albumin to enter what via what?

• myocytes

• specific transporters i.e., fatty acid transporters

Once in the myocyte, fatty acids undergo what?

• beta-oxidation

Beta-oxidation

• fatty acid → CO2

• provides ATP

  • fuels muscle cells

Lipases cleave fatty acids from…?

• glycerol backbone of triacylglycerols

Glycerol kinase activates glycerol at the expense of what allowing what?

• ATP

• allows limited anaerobic catabolism of fats

Entry of glycerol into the glycolytic pathway

• glycerol phosphorylation via ATP

• glycerol oxidized to the glycolytic intermediate dihydroxyacetone phosphate

• DHAP continues through glycolysis

Enzymes necessary for fatty acid oxidation in animal cells are found where?

• mitochondrial matrix

Fatty acids with chains 12 or less carbons long can what?

• readily enter the mitochondria for oxidation

Fatty acids larger than 12 carbons i.e., > 14 require what to enter the mitochondria?

• carnitine shuttle

• can’t directly enter

• most fatty acids from diet and stored ones

Fatty acid activation and transport to mitochondria step 1

• converted to fatty acyl CoA

• outer mitochondrial membrane

What enzyme catalyzes the conversion of fatty acid → fatty acyl CoA?

• fatty acyl CoA synthetase

Fatty acyl-CoAs are high or low energy compounds?

• high

• like acetyl-CoAs

The conversion of fatty acid → fatty acyl-CoA is couple with what?

• ATP hydrolysis → AMP + 2Pi

• large negative standard gibbs free energy change

• drives reaction forward

Fatty acyl CoA synthesized in the cytosolic side of the mitochondrial membrane can be one of two things…what are they?

• transported to mitochondria → oxidation

• used in cytosol → synthesize membrane lipids

What is the regulatory step of fatty acid oxidation?

• fatty acid → fatty acyl CoA

There are different isoforms of fatty acyl CoA synthetase, why?

• different kinds of fatty acids i.e., short, long chains

After fatty acyl-CoA is formed at the outer membrane/cytosol what happens?

• moved to mitochondrial matrix via facilitated diffusion

Fatty acyl-CoA binds to what forming what to enter the mitochondrial matrix?

• carnitine

• fatty acyl-carnitine shuttle

What enzyme is responsible for catalyzing the binding of carnitine and fatty acyl-CoA?

• carnitine acyltransferase

Fatty acyl-carnitine formed in the outer mitochondrial membrane is shuttled where? through what structures?

• intermembrane space (IMS)

• large protein pores

Fatty acyl-carnitine then moves from the IMS to where? via what transporter?

• mitochondrial matrix

• acyl carnitine/acyl transporter

  • located in inner mitochondrial membrane

Once fatty acyl-carnitine is inside the matrix, what is it transferred onto? what does it release?

• coenzyme A

• releases carnitine

What enzyme catalyzes the transfer of fatty acyl onto coenzyme A releasing carnitine?

• carnitine acyltransferase II

What happens to the carnitine once it is released from the fatty acyl?

• returns back for another cycle of fatty acyl transfer into the matrix

Stage 1 of fatty acid oxidation

• oxidative conversion of 2-C units into acetyl-CoA

• release of NADH

Stage 2 of fatty acid oxidation

• oxidation of acetyl-CoA into CO2 via citric acid cycle

• release of NADH & FADH2

Stage 3 of fatty acid oxidation

• generates ATP from NADH and FADH2 via respiratory chain

  • ETC

  • OXPHOS

Each step of beta-oxidation results in the release of what from where?

• one acetyl residue

• carboxyl end of fatty acyl chain

B-oxidation is a what sequence?

• 4 step

Palmitoyl-CoA has a 16-C long chain, meaning it releases how many acetly-CoAs?

• 8 acetyl-CoAs

Step 1) Dehydrogenation of fatty acvyl-CoA

• forms double bond between alpha and beta carbons (C2 and C3)

• reduces FAD to FADH2

• makes trans enoyl-CoA

What enzyme catalyzes the first dehydrogenation step of beta oxidation?

• acyl-CoA dehyrogenase

All isozymes of the acyl-CoA dehydrogenase enzyme have what as a prosthetic group?

• FAD

3 different isozymes of acyl-CoA dehydrogenase can be used, why?

• different chain lengths

• recall:

  • VLCAD → long i.e., 12 - 18

  • MCAD → medium i.e., 4 - 14

  • SCAD → short i.e., 4 - 8

FAD is reduced to FADH2 during the dehydrogenation step of B-oxidation, what’s the purpose of this?

• electrons from FADH2 passed onto ETC via electron transferring flavoprotein (ETF)

Step 2) Hydration to alkene

• water added to double bond from step 1

  • trans enoyl-CoA

What enzyme catalyzes the hydration step of B-oxidation?

• enoyl-CoA hydratase

What is the hydration step of B-oxidation analogous to in another cycle?

• fumarase reaction in citric acid cycle

The hydration step is catalyzed by two isoforms of enoyl-CoA hydratase, what are they?

• soluble short chain hydratase

  • crotonase

• membrane-bound long chain hydratase

  • trifunctional complex

Can enoyl-CoA hydratase catalyse unsaturated fatty acid chains?

• no

• not a substrate for the enzyme