Biochem Of Met, Block 2, # 4 And 5: Lipid Metabolism

Front 1

What kinds of lipids are there, and what are their general functions?

Back 1

Lipds can be in the form of:

Fatty Acids and Triglycerides: storage of energy.

Sterols/phospholipids (make up membranes)

Lots of other functions

Front 2

Fatty Acids - what's their structure? what is saturated/unsaturated? what's the nomenclature all about?

what does 18:1 delta 9 cis-9-octadecenoic acid mean?

Back 2

Carboxyl group with long hydrocarbon chain (12-24 C's).

Carboxyl carbon is not counted, next one is alpha, next one is BETA, and this is where oxidation happens.

Saturated = no double bonds/
Unsaturated = some double bonds

nomenclature:
18 total carbons, 1 double bond at the 9th (between 9 and 10).

Front 3

Where are fatty acids used? ketone bodies?

Back 3

FA's used by liver, muscle, heart

Ketones used by brain.

Front 4

What's the structure of a triglyceride? Where is it stored?

Back 4

Usually 3 FA's bound to glycerol. The middle chain can be the unsaturated one. This is what is stored in adipocytes.

Front 5

What kinds of fatty acids are in our foods?

Back 5

LMPS.

Lauric acid (c12) - coconut/palm/breast milk

Myristic acid (c14) - dairy

Palmitic acid (c16) - palm oil and meat

Stearic acid (c18) - meat coca butter.

Front 6

What kinds of mono/poly unsaturated fats do we eat?

What's partial hydrogenation?

What fat must come from diet?

Back 6

most vegetables have polyunsaturated, most meats are saturated or monounsaturated.

fluidity goes up with the number of double bonds = unnsaturated = fluid.

Partial hydrogenation removes double bonds, makes fats more solid and improves shelf life. Also adds TRANS double bonds, which are bad.

Linolenic acid has to come from the diet. It's an OMEGA 3.

Front 7

Fat in diet - how is it packaged and where does it go?

Back 7

packaged into CHYLOMICRONS with phospholipid membrane.

They're transported to muscle and fat cells.

Front 8

What happens to CHYLOMICRONS when they're empty?

Back 8

remnant chlorymicrons are sent to liver where remaining FA's are converted to ketone bodies.

If there are already a lot of FA's, make VLDL's, LDL's, or HDL's and put back into blood to carry FA's to fat cells for storage.

Know that chylomicrons are very NOT dense and have lots of FA's,

VLDL's are the next non-densest and have a little fewer FA's

LDL's are the next non-densest and have a little fewer FA's.

HDL's are the most non-dense (highest density) and carry the fewest FA's.

Front 9

How are FA's mobilized when energy is needed?

Back 9

Lipid droplets covered in PERILIPIN. Hormone signal activates cAMP/PKA which phosphos the perilipin and a LIPASE, which gets access to the triglyceride. Lipase hydrolyzes into free fatty acids.

fFA's bind to a passing serum-albumen and get carried to a far away tissue.

Front 10

what signals for the release of FA's from adipose tissues, and how does it work?

Back 10

low glucose/high glucagon/epinephrine= activate pKA, phosphorylate perilipins and lipases.

lipase get access to lipids and hydrolyze off the glycerol, making free fatty acids, which go into serum albumen and travel around.

Front 11

Fatty Acid ß-oxidation: what's the first step? What does geography have to do with it?

Back 11

Must "activate" the fatty acid into fatty acyl-CoA. If this happens in the cytosol, the product is destined to be in the membrane.

if it happens in the mito, it's going to be used for ß oxidation.

first step is catalyzed by fatty acyl-CoA Synthetase.

Front 12

Fatty Acid ß-oxidation: what's the second step? why is it unique?

Back 12

this commits the FA to oxidation, and involves the CARNITINE SHUTTLE.

Have to get across BOTH mito membranes, have a carnitine in each.
Carnitine Acyltransferase I is in the outer, Acyltransferase II is in the inner. Also a transporter complex.

1. Acyltransferase I forms acylcarnitine (AC), ditches the CoA, which moves across the intermembrane space, gets transported across the inner membrane.

2. Acyltransferase II adds back on a DIFFERENT CoA (2 pools, one in, one out) and releases for ß oxidation.

Front 13

Beta oxidation: what kinds of reactions happen, and in what order?

Back 13

4 repeated reactions:
oxidation
hydration
oxidation
cleavage (thiolysis from S group in CoA)

Front 14

What's produced in one round of beta oxidation?

Back 14

1st rxn = 1 FADH2
3rd rxn = 1 NADH

also get an acetyl Co-A

Front 15

What enzymes are used in beta oxidation?

Back 15

1. Acyl Co-A dehydrogenase

2. Enolyl CoA hydrase

3. Beta hydroxy acyl CoA Dehydrogenase

4. acyl Co A acetyltransferase (thiolase)

Front 16

How much energy is made from a round of beta oxidation? how do we figure this out for a chain of certain length (16, for example?)

Back 16

If 16 long, going to get 8 acetyl CoA's out (2 carbons each). Each acetyl CoA will make 10 ATP, so total here is 80 ATP from acetyl CoA.

Note that there will be total/2 - 1 number of rounds of beta oxidation, so in this example, 16/2 = 8, 8-1 =7.

So, 7 rounds = 7 FADH2 and 7 NADH. Remember each FADH2 = 1.5 ATP, and each NADH = 2.5 ATP.

Front 17

What disease should we associate with carnitine?

Back 17

Primary Carnitine Deficiency: autosomal recessive. Shows up in infancy.

Seen during periods of fasting (viral infection, etc) - can't use fats for energy. Confused, coma, encephalopathy, hypoglycemia.

Can treat with carnitine supplementation.

Front 18

What happens if the FA undergoing ß oxidation has 1 double bond in it (is not saturated)? AKA MONOunsaturated.

Back 18

Proceed normally to the double bond, then use:

*Enoyl CoA Isomerase*

Turns the CIS double bond to TRANS. This is exactly how it looks in the normal 2nd step of ß-oxidation, so it proceeds normally.

NOTE: because 1st step is being skipped, no FADH2 is made in this round!

Front 19

Oxidation of polyunsaturated fats: what's up?

Back 19

Still use the enoyl Co-A isomerase above, but immediately after, also use a reductase: it's NADPH dependent, and called 2,4 Dienoyl-CoA reductase.

Front 20

oxiation of odd chain length fatty acids: what's up?

Back 20

last 3 carbons make a 3 carbon little guy called propionyl CoA. This gets turned into methyl,alonylCoA, which then gets turned into Succnyl CoA using B12.

Also get same thing from BRANCHED CHAIN Fa's.

Front 21

What about very long fatty acids?

Back 21

Need to be digested in the perioxisome. These come from sphingolipids, usually.

No Carnitine.

Make Trans- enoyl CoA and FADH2, which then becomes hydrogen peroxide H202.

Front 22

What about branched chain FA's?

Back 22

Branched chains: two kinds naturally, phytanic acid and pristanic acid (made by chlorophyll).

Do ALPHA oxidation in the PERIXOISOME. Do lots of normal beta oxidation, then get each individual branch makes one propinyl CoA.

Front 23

What branched chain disease should we think of?

Back 23

Refsum's disease: genetic defect in phytanoyl-CoA hydroxylase, so get no alpha oxidation, and big buildup of phytanic acid. Bad brain problems.

Front 24

Where can omega oxidation happen?

Back 24

In the ER, used for 10-12 C length FA's. Minor.

Front 25

What disease should we think about with medium length FA's?

Back 25

MCAD : medium chain acyl-CoA dehydrogenase deficiency. These FA's are 6-12 in length.

1 in 40 are carriers, 1/1000 incidence.

see accumulation of fat in liver, low blood glucose, lots of 6-10 C FA's in urine. Treat with low fat high carb diet.

Front 26

When doing beta oxidation in the liver of FA's, what happens with the acetyl CoA generated? Then what?

Back 26

Generation of ketone bodies happens here, then they're oxidized in the muscles.

these are converted to ketone bodies (via beta hydroxybuterate and aceto-acetate)

These ketone bodies are shuttled around and then re-converted back to acetyl CoA for ATP generation.

Front 27

When making ketone bodies in the liver, what's the general scheme?

How about oxidizing them in the tissues?

Back 27

Go from 2 acetyl CoA's to AcetyoAcetyl CoA, then loose the CoA, then make beta hydroxy buterate. Note that a certain amount of acetone is a byproduct here.

In the tissues, do the opposite-
beta hydroxy buterate to acetoacetate,

to acetoacetyl CoA

to Acetyl Co A

Front 28

Fatty Acid Synthesis: what's the 2 carbon precursor?

Back 28

ultimately, it comes from acetyl Co-A, which becomes "tagged" and permanently reassigned by becoming malonyl Co A.

Note that malonyl CoA is 3 carbons long - it takes a C02 to make, a c02 which is then removed during assembly of the FA.

Front 29

Geography: where do fatty acid beta oxidation and synthesis take place?

Back 29

fatty acid synthesis happens in CYTOPLASM, beta oxidation happens inthe mitochondrial matrix!

Front 30

How is acetyl Co A turned into malonyl Co A?

Back 30

ACC complex (acetyl Co A Carboxylase), which is TRIfunctional:

biotin carrier, biotin carboxylase, and biotin transcarboxylase.

Bifnctional enzyme: biotin transcarboxylase and then carboxylase.

Biotin Transcarboxylase binds CO2 and activates it (THIS USES ATP), then the transcarboxylase end transfers the CO2 to acetyl Co-A, making malonyl Co A.

Front 31

Once you have malonyl CoA, what kinds of reactions assemble a FA?

Back 31

Reverse of beta oxidation.

CRDR.
Condensation
Reduction
Dehydration
Reduction

Front 32

What things are made during FA assembly?

Back 32

A C02 is taken out of the reaction in step 1, an NADH to NAD+ happens in reaction 2, and an NADPH to NADP+ happens in step 4.

Front 33

What is a major product of FA synthesis, and what does it look like?

What can be done with it? Saturate?

Back 33

Palmate (16 carbons) - Each round of assembly costs 2 NADPH, makes 1 CO2.

Further modification to serate and past is totally possible using the FA elongation system and malonyl-CoA, though it doesn't use the ACP system.

Double bonds can be added (desaturation) via FA CoA Desaturase, making H20.

Front 34

Once fatty acids are created, what can be done with them? What enzymes are used, and what's produced?

Back 34

Have to turn into triglycerides, which are either stored or used as membrane components.


Want to esterify the FA's to Glycerol-3-phosphate. Need to first generate it:

dhap to g3p via G-3-P dehydrogenase

or
glycerol to G3p via glycerol kinase

Next, need to add the acyl chains: use Acyl CoA Synthase

This makes PHOSPHOTIDIC ACID.

Then add a polar head group (glycerophospholipid) or attach another acyl group to make a triglyceride.

Front 35

What's the story behind cox inhibitors? What two big ones are there?

Back 35

Phospholipids have arachidonate in them - hormones/inflamation causes the release of this into the cell, and then SER converts them to prostiglandins, which can cause pain. ECOSINOIDS are a type of prostiglandin.

Cyclooxygenase (COX) mediates this conversion to prostiglandins.

Asprin blocks Cox1 and 2, causes stomach upset - ibuprofen blocks Cox2 and is better tolerated.

Front 36

How is fatty acid synthesis up regulated (beta oxidation down?)

Back 36

Glucose is big.

Big thing is Malonyl CoA to Acetyl CoA ratio. Remember that malonyl CoA is locked into FA synthesis.

This means that ACC (acetyl CoA carboxylase makes malonyl CoA) and acetyltransferase I (carnitine movement of FA into mito for beta oxidation) are opposing each other.

High blood sugar = up insulin = dephospho ACC and activate it (this turns acetyl CoA to malonyl CoA), make FA's. Malonyl CoA inhibits acyltransferase I

Front 37

How is FA synthesis down regulated (beta oxidation up?)

Back 37

Low glucose = up glucagon = phospho ACC = turn it off, so not making malonyl CoA.

Malonyl COA drops and stops inhibiting acyltrasferase I, so movement of FA into mito = beta oxidation.

Front 38

How do FA's affect use of glucose?

Back 38

In low glucose state, muscle/fat cells start using fatty acids preferentially. FA use makes lots of NADH, lots of FADH2, lots of acetyl CoA and lots of ATP - all this inhibits PFK-1 and stops glycolysis.

G-6-P builds up, stops hexokinase, stops glucose entry into cells, saves it for nerves/brain.

Front 39

What are Leptin and adiponectin?

Back 39

Leptin is released by adipocytes as FA levels rise, act through jak/stat in hypothalmus to signal cessation of eating.

Adiponectin produced by fat cells and helps regulate glucose/FA entry into cells and their use.

Front 40

What happens in obese people that causes insulin resistance?

Back 40

Adiponectin release is inhibited as fat cells grow - so fatties have less of it floating around. This means they can't use FA's and glucose as well as they could before, and this is insulin resistance.

Find free FA's in type 2 diabetics blood. These also might mess with beta cells.

Front 41

Fatty Acid Synthesis: what's the cost of each subunit?

Back 41

each subunit is 2 carbons, and comes from malonyl CoA.

Each 2-carbons costs 1 malonyl CoA, costs 2 NADPH's, and makes 1 Co2

Front 42

FA synthesis: once you have malonyl CoA, what kinds of reactions are used? Where does this happen and on what?
What are the names of the enzymes?

Back 42

CRDR: condensation, reduction, dehydration, reduction. This will cost 2 NADPH's, make a CO-2, and cost 1 acetyl CoA.

Enzymes used:
BK/BH/BH/E

Beta keto Acyl ACP Synthase
Beta hydroxy acy ACPl reductase
Beta hydroxy dehydrase
Enoyl ACP reductase