Metabolism Lecture 15

Front 1

Fatty acids are stored in the form of

Back 1

trigylcerides are the storage form of...

Front 2

Fatty acids are stored as triglycerides in ...

Back 2

adipocytes (comprised primarily of)

Front 3

Steps of Fatty Acid Storage

Back 3

3 Step Process:
1. Circulating plasma lipoprotein triglyceride (in VDL from de novo FA from liver, in chylomicrons if injested FA) converted by Lipoprotein lipse into Fatty Acid + Glycerol

VLDL or chylomicron Triglyceride ---> FA + glycerol

2. FA uptake into adipocyte (via CD36 protein??)

3. Fatty Acid reesterfication to trigylceride

FA (as fatty acyl-CoA) + Glycerol-3-Phospate ---) Trigylceride + CoA + Pi

Front 4

lipoprotein lipase

Back 4

converts plasma lipoprotein triglyceride (in VLDL or chylomicrons)

into

Fatty acid + Glycerol

Front 5

lipoprotein lipase is synthesized where?

Back 5

synthesized in adipocyte,

then translocated to an EC location (on surface of capillary endothelium) where it can act on circulating lipoproteins

Front 6

Protein responsible for fatty acid uptake into adipocyte

Back 6

CD36???

Front 7

Injested Fatty Acid circulates as

Back 7

plasma lipoprotein in chylomicrons

Front 8

Fatty Acid synthesized (de novo) by liver circulates as ....

in what?

Back 8

plasma lipoprotein

in very light density lipoprotein VLDL?

Front 9

fatty acids are mobilized from adipose tissue via...

Back 9

activation of lipases
(mobilizes FAs)

Front 10

lipases important in mobilizing FAs

Back 10

within adipocyte: (adipose TG --> FA)
adipose trigylceride lipase (ATGL)
hormone-sensitive lipase (HSL)
(*HSL major)

Lipoprotein lipase (LPL):
lipoprotein TG ---> FA

Pancreatic Lipase:
ingested TG --> FA (& DG & MG)

Front 11

fatty acid mobilization from adipose tissue involves which lipases?

Back 11

ATGL
HSL (MAJOR)

**notes, ATGL may be major TG lipase
whereas HSL may be major DG/MG lipase

Front 12

Fatty Acids mobilized by lipases circulate bound to...

Back 12

serum albumin

Front 13

FFA

Back 13

Free Fatty Acids (those circulating in plasma bound to albumin)

aka: NEFA (non-esterified fatty acids)

Front 14

Free Fatty Acids are available:

Back 14

as oxidative fuel to several tissues

also can be converted into "ketone bodies" in the liver

Front 15

glycerol released by adipocyte
via what kind of protein?
what is it available to do?

Back 15

exits via aquaporin

available as a gluceogenic precursor in the liver and kidney

Front 16

When and
by what

are ATGL and HSL regulated?

Back 16

highly regulated during fasting/feeding

regulated by a # of hormones/cytokines both:
at the level of gene expression
and
via covalent enzyme phosphorylation

Front 17

HSL

Back 17

hormone-sensitive lipase

involved in the breakdown of trigylcerides (within adipose cells) into FAs and glycerol + 3 H+

Front 18

ATGL

Back 18

adipose triglyceride lipase

involved in the breakdown of trigylcerides (within adipose cells) into FAs and glycerol + 3 H+

Front 19

perilipin

Back 19

portein sturrounding lipid droplet that positions HDL/ATGL

Front 20

Glycerol exits adipocyte via

Back 20

Aquaporin-7

Front 21

Fatty Acyl-CoA Ligases

Back 21

catalyze the formation of the fatty acyl thioester conjugate with Coenzyme A

Fatty Acid + ATP <--> Fatty acyl adenylate + 2Pi

Fatty acyl adenylate + CoA-SH <--> Fatty acyl-CoA + AMP + H+

Front 22

CD36

Back 22

protein that appears to be involved in faty acid uptake by cells

also important in "tasting" fat in the taste buds of the tongue

Front 23

Fatty Acid Oxidation occurs in:

Back 23

occurs in all tissues except for:
the brain and RBCs

Front 24

Role of FA oxidation in Liver

Back 24

supplies ATP necessary for gluconeogenesis and other hepatic functions

Front 25

Role of FA oxidation in muscle (cardiac and skeletal)

Back 25

FAs in muscle are the preferred fuel for oxidative metabolism

Front 26

Fatty Acid oxidation takes place ...

Back 26

in the midochondria

Front 27

How do fatty acids get into mitochondria?

Back 27

using ATP

reaction catalyzed by Fatty Acyl-CoA ligases sticks a CoA onto FA via thioester bond

FA + ATP <--> Fatty acyl Adenylate <--> Fatty acyl-CoA

(**occurs in outer mito membrane)

Front 28

How do fatty acids go from outer mitochondrial membrane into mitochondrial matrix?

Back 28

Fatty acyl-CoA (generated via Fatty Acyl-CoA ligase) undergoes Ester VoA switch with carnitine

Fatty acyl-CoA + carnitine <--> CoA + Acyl Carnitine

Acyl Carnitine can be transferred via CAT-I into matrix

Front 29

CAT-I

Back 29

carnitine acyltransferase I

enzyme that catalyzes transesterfication reaction on outer surface of inner mitochondrial membrane (fatty acyl-co + carnitine --> acyl carnitine + CoA

(acyl carnitine can enter matrix via translocase?

Front 30

CAT-II

Back 30

catalyzes transesterification reaction of matrix side of inner mito membrane

acyl carnitine + CoA --> acyl CoA + carnitine

(carnitine can exit matrix via translocase)

Front 31

carnitine

Back 31

zwitterionic compound derived from lysine

facilitates fatty acid transport into mitochondrial matrix by conjucation to fatty acid moiety catalyzed by CAT I

CAT II switches the FA to CoA allowing carnitine to exit matrix via translocase

Front 32

key step in oxidation of fatty acid

Back 32

FORMATION and TRANSLOCATION of Fatty-Acyl Carnitine (gets FA into mitochondrial maxtrix!)

Front 33

Regulation of CAT I

Back 33

allosterically inhibited by:
malonyl CoA (product of ACC(beta))

Front 34

what is the relationship between the rate of FA synthesis and FA oxidation?

how is this relationship established?

Back 34

inverse and coordinate relationship
if malonyl-CoA is present;
FAs are being made
don't want to oxidize FAs
CAT I allosterically inhibited
acyl CoA can't get into matrix
can't be oxidized

this regulation established by this "coordinate" allosteric inhibition of CAT I by malonyl-CoA (the product of the acetyl-CoA carboxylase reaction)

this inhibition provides switching mechanism bt glucose and FA oxidation

Front 35

when glucose is present:
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:

Back 35

glycolytic rates are: HIGH
malonyl CoA levels are: HIGH
fatty acids are: NOT OXIDIZED (as much)

Front 36

when glucose is relatively unavailable
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:

Back 36

glycolytic rates are: LOW
malonyl CoA levels are: LOW
fatty acids are: OXIDIZED (as much)

Front 37

How is fatty acyl-CoA reformed in matrix?

Back 37

CAT II (carnitine acyltransferase II)

carnitine acyltransferase catalyzes reaction where acyl is switched back to a CoA from the carnitine molecules

Front 38

ACC-Beta

Back 38

helps tissues decide whether to use glucose or FAs

if glucose is available
ACCbeta is active
malonyl-CoA is produced
malonyl-CoA allosterically inhibits CAT I
inhibition of CAT I prevents acyl CoA from entering matrix


oxidation of FAs is inhibited

ACCbeta is an:
Isozyme of acetyl-CoA carboxylase

Front 39

What happens when mice don't have ACCbeta?

Back 39

High Food intake
Low body weight

due to higher rate of FA oxidation
because malonyl CoA production insufficient to inhibit CAT I

Front 40

Beta oxidation

Back 40

inside mito matrix:
fatty acyl-CoAs can be oxidized
(initially at the beta carbon)
followed by a series of steps that:
release 2 carbon fragments in the
form of acetyl-CoA

Front 41

1st step of Beta Oxidation

hint: Initial dehydrogenase reaction

Back 41

Acyl CoA oxidzed at beta carbon
FAD reduced to FADH2

Front 42

2nd step of Beta Oxidation

Back 42

hydration

Front 43

3rd step of Beta oxidation

Back 43

oxidation (2nd degydrogenation reaction)
formation of NADH

Front 44

in beta oxidation each palmitoyl-CoA undergoes:

Back 44

7 oxidation cycles
yielding 8 acetyl-CoAs

Front 45

products of beta oxidation of FAs available for the ETC

Back 45

each cycle yields:
FADH2 (from first hydrogenase reaction
NADH (from 2nd hydrogenase reaction)

Front 46

carnitine

Back 46

zwitterionic compound derived from lysine

facilitates fatty acid transport into mitochondrial matrix by conjucation to fatty acid moiety catalyzed by CAT I

CAT II switches the FA to CoA allowing carnitine to exit matrix via translocase

Front 47

key step in oxidation of fatty acid

Back 47

FORMATION and TRANSLOCATION of Fatty-Acyl Carnitine (gets FA into mitochondrial maxtrix!)

Front 48

Regulation of CAT I

Back 48

allosterically inhibited by:
malonyl CoA (product of ACC(beta))

Front 49

what is the relationship between the rate of FA synthesis and FA oxidation?

how is this relationship established?

Back 49

inverse and coordinate relationship
if malonyl-CoA is present;
FAs are being made
don't want to oxidize FAs
CAT I allosterically inhibited
acyl CoA can't get into matrix
can't be oxidized

this regulation established by this "coordinate" allosteric inhibition of CAT I by malonyl-CoA (the product of the acetyl-CoA carboxylase reaction)

this inhibition provides switching mechanism bt glucose and FA oxidation

Front 50

when glucose is present:
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:

Back 50

glycolytic rates are: HIGH
malonyl CoA levels are: HIGH
fatty acids are: NOT OXIDIZED (as much)

Front 51

when glucose is relatively unavailable
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:

Back 51

glycolytic rates are: LOW
malonyl CoA levels are: LOW
fatty acids are: OXIDIZED (as much)

Front 52

How is fatty acyl-CoA reformed in matrix?

Back 52

CAT II (carnitine acyltransferase II)

carnitine acyltransferase catalyzes reaction where acyl is switched back to a CoA from the carnitine molecules

Front 53

ACC-Beta

Back 53

helps tissues decide whether to use glucose or FAs

if glucose is available
ACCbeta is active
malonyl-CoA is produced
malonyl-CoA allosterically inhibits CAT I
inhibition of CAT I prevents acyl CoA from entering matrix


oxidation of FAs is inhibited

ACCbeta is an:
Isozyme of acetyl-CoA carboxylase

Front 54

What happens when mice don't have ACCbeta?

Back 54

High Food intake
Low body weight

due to higher rate of FA oxidation
because malonyl CoA production insufficient to inhibit CAT I

Front 55

Beta oxidation

Back 55

inside mito matrix:
fatty acyl-CoAs can be oxidized
(initially at the beta carbon)
followed by a series of steps that:
release 2 carbon fragments in the
form of acetyl-CoA

Front 56

1st step of Beta Oxidation

hint: Initial dehydrogenase reaction

Back 56

Acyl CoA oxidzed at beta carbon
FAD reduced to FADH2

Front 57

2nd step of Beta Oxidation

Back 57

hydration

Front 58

3rd step of Beta oxidation

Back 58

oxidation (2nd degydrogenation reaction)
formation of NADH

Front 59

in beta oxidation each palmitoyl-CoA undergoes:

Back 59

7 oxidation cycles
yielding 8 acetyl-CoAs

Front 60

products of beta oxidation of FAs available for the ETC

Back 60

each cycle yields:
FADH2 (from first hydrogenase reaction
NADH (from 2nd hydrogenase reaction)

Front 61

what happens to 8 acetyl-CoAs formed from beta oxidation of a palmitoyl-CoA

Back 61

IF:
sufficient oxaloacetate is present (requires some continued oxidation of glucose)

8 acetyl-CoAs formed from beta oxidation pathway are available for complete combustion in the TCA cycle

Front 62

why is glucose necessary for acetyl-CoA to enter TCA cycle

Back 62

need oxaloacetate

Front 63

Energy Yields from Beta Oxidation of Fatty Acids

Back 63

NET ATP PRODUCED: 106 mol/ palmitate

-Metabolism of 8 mol acetyl-CoA in Krebs cycle: + 80 mol ATP
-Oxidation of 7 mol FADH2 (ubiquinone): 10.5 mol ATP
-Oxidation of 7 mol NADH (NADH hydrogenase): + 17.5 mol ATP
-ATP utilization in fatty acyl-CoA ligase: -2 mol ATP

Front 64

why is conversation of FAs to ketone bodies critical?

Back 64

creates a water-soluble oxidative fuel out of one that is only lipid soluble

Front 65

ketone bodes are utilized by:

Back 65

principally by: muscle (esp. the heart and skeletal msucle)

can also be made available to brain (FAs are not bc they can't pass blood brain barrier)

Front 66

Ketogenesis occurs where?

Back 66

only in the liver

Front 67

ketone bodies

Back 67

acetoacetate and beta-hydroxybutyrate

organic acids, can cause acidosis if they accumulate in excess in plasma

Front 68

under what conditions are ketone bodies produced?

Back 68

when levels of oxaloacetate are low (glucose unavailable)
conversion of acetyl-CoA to citrate (catalyzed by citrate synthase) is low

so...
acetyl CoA is disposed of via pathway that generates ketone bodies

Front 69

in the absence of glucose acetyl CoA is disposed via pathway in LIVER that generates:

Back 69

ketone bodies (acetoacetate and beta-hydroxybutyrate)

some acetone also formed (by spontaneous decarboxylation)

Front 70

fate of acetoacetate and beta hydroxybuyrate in non-hepatic tissues:

Back 70

reconverted to acetoacetyl-CoA, which is then converted to acetyl CoA for combustion in the TCA cycle

MITOCHONDRIA ARE REQUIRED FOR KETONE OXIDATION

Front 71

products of Ketogenesis (and destination)

Back 71

Ketone Bodies: (to skeletal muscle, heart and brain)
Acetoacetate
Beta Hydroxybutyrate

Acetone: (to lungs)
expired, can be smelled in breath

Ketones in urine indicative of ketogenesis

Front 72

how can one detect ketogenesis

Back 72

breathe smells of acetone

ketones in urine

Front 73

why can't glucose be made from Fatty Acids

Back 73

PDH reaction IRREVERSIBLE
acetyl-CoA derived from beta oxidation
cannot form pyruvate
NO NET SYNTHESIS of OXALOACETATE in TCA CYCLE:
although acetyl-coA can be used to spin Kreb cycle, carbons are lost- so can't get net glucose production

Front 74

If No glucose is ingested:
Insulin levels:
Rate of FA synthesis:
Metabolism of FA:

Back 74

Insulin levels: LOW
Rate of FA synthesis: LOW
Metabolism of FA: INCREASED