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74 Cards in this Set

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Fatty acids are stored in the form of
trigylcerides are the storage form of...
Fatty acids are stored as triglycerides in ...
adipocytes (comprised primarily of)
Steps of Fatty Acid Storage
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
lipoprotein lipase
converts plasma lipoprotein triglyceride (in VLDL or chylomicrons)

into

Fatty acid + Glycerol
lipoprotein lipase is synthesized where?
synthesized in adipocyte,

then translocated to an EC location (on surface of capillary endothelium) where it can act on circulating lipoproteins
Protein responsible for fatty acid uptake into adipocyte
CD36???
Injested Fatty Acid circulates as
plasma lipoprotein in chylomicrons
Fatty Acid synthesized (de novo) by liver circulates as ....

in what?
plasma lipoprotein

in very light density lipoprotein VLDL?
fatty acids are mobilized from adipose tissue via...
activation of lipases
(mobilizes FAs)
lipases important in mobilizing FAs
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)
fatty acid mobilization from adipose tissue involves which lipases?
ATGL
HSL (MAJOR)

**notes, ATGL may be major TG lipase
whereas HSL may be major DG/MG lipase
Fatty Acids mobilized by lipases circulate bound to...
serum albumin
FFA
Free Fatty Acids (those circulating in plasma bound to albumin)

aka: NEFA (non-esterified fatty acids)
Free Fatty Acids are available:
as oxidative fuel to several tissues

also can be converted into "ketone bodies" in the liver
glycerol released by adipocyte
via what kind of protein?
what is it available to do?
exits via aquaporin

available as a gluceogenic precursor in the liver and kidney
When and
by what

are ATGL and HSL regulated?
highly regulated during fasting/feeding

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

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

involved in the breakdown of trigylcerides (within adipose cells) into FAs and glycerol + 3 H+
perilipin
portein sturrounding lipid droplet that positions HDL/ATGL
Glycerol exits adipocyte via
Aquaporin-7
Fatty Acyl-CoA Ligases
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+
CD36
protein that appears to be involved in faty acid uptake by cells

also important in "tasting" fat in the taste buds of the tongue
Fatty Acid Oxidation occurs in:
occurs in all tissues except for:
the brain and RBCs
Role of FA oxidation in Liver
supplies ATP necessary for gluconeogenesis and other hepatic functions
Role of FA oxidation in muscle (cardiac and skeletal)
FAs in muscle are the preferred fuel for oxidative metabolism
Fatty Acid oxidation takes place ...
in the midochondria
How do fatty acids get into mitochondria?
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)
How do fatty acids go from outer mitochondrial membrane into mitochondrial matrix?
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
CAT-I
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?
CAT-II
catalyzes transesterification reaction of matrix side of inner mito membrane

acyl carnitine + CoA --> acyl CoA + carnitine

(carnitine can exit matrix via translocase)
carnitine
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
key step in oxidation of fatty acid
FORMATION and TRANSLOCATION of Fatty-Acyl Carnitine (gets FA into mitochondrial maxtrix!)
Regulation of CAT I
allosterically inhibited by:
malonyl CoA (product of ACC(beta))
what is the relationship between the rate of FA synthesis and FA oxidation?

how is this relationship established?
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
when glucose is present:
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:
glycolytic rates are: HIGH
malonyl CoA levels are: HIGH
fatty acids are: NOT OXIDIZED (as much)
when glucose is relatively unavailable
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:
glycolytic rates are: LOW
malonyl CoA levels are: LOW
fatty acids are: OXIDIZED (as much)
How is fatty acyl-CoA reformed in matrix?
CAT II (carnitine acyltransferase II)

carnitine acyltransferase catalyzes reaction where acyl is switched back to a CoA from the carnitine molecules
ACC-Beta
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
What happens when mice don't have ACCbeta?
High Food intake
Low body weight

due to higher rate of FA oxidation
because malonyl CoA production insufficient to inhibit CAT I
Beta oxidation
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
1st step of Beta Oxidation

hint: Initial dehydrogenase reaction
Acyl CoA oxidzed at beta carbon
FAD reduced to FADH2
2nd step of Beta Oxidation
hydration
3rd step of Beta oxidation
oxidation (2nd degydrogenation reaction)
formation of NADH
in beta oxidation each palmitoyl-CoA undergoes:
7 oxidation cycles
yielding 8 acetyl-CoAs
products of beta oxidation of FAs available for the ETC
each cycle yields:
FADH2 (from first hydrogenase reaction
NADH (from 2nd hydrogenase reaction)
carnitine
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
key step in oxidation of fatty acid
FORMATION and TRANSLOCATION of Fatty-Acyl Carnitine (gets FA into mitochondrial maxtrix!)
Regulation of CAT I
allosterically inhibited by:
malonyl CoA (product of ACC(beta))
what is the relationship between the rate of FA synthesis and FA oxidation?

how is this relationship established?
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
when glucose is present:
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:
glycolytic rates are: HIGH
malonyl CoA levels are: HIGH
fatty acids are: NOT OXIDIZED (as much)
when glucose is relatively unavailable
glycolytic rates are:
malonyl CoA levels are:
fatty acids are:
glycolytic rates are: LOW
malonyl CoA levels are: LOW
fatty acids are: OXIDIZED (as much)
How is fatty acyl-CoA reformed in matrix?
CAT II (carnitine acyltransferase II)

carnitine acyltransferase catalyzes reaction where acyl is switched back to a CoA from the carnitine molecules
ACC-Beta
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
What happens when mice don't have ACCbeta?
High Food intake
Low body weight

due to higher rate of FA oxidation
because malonyl CoA production insufficient to inhibit CAT I
Beta oxidation
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
1st step of Beta Oxidation

hint: Initial dehydrogenase reaction
Acyl CoA oxidzed at beta carbon
FAD reduced to FADH2
2nd step of Beta Oxidation
hydration
3rd step of Beta oxidation
oxidation (2nd degydrogenation reaction)
formation of NADH
in beta oxidation each palmitoyl-CoA undergoes:
7 oxidation cycles
yielding 8 acetyl-CoAs
products of beta oxidation of FAs available for the ETC
each cycle yields:
FADH2 (from first hydrogenase reaction
NADH (from 2nd hydrogenase reaction)
what happens to 8 acetyl-CoAs formed from beta oxidation of a palmitoyl-CoA
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
why is glucose necessary for acetyl-CoA to enter TCA cycle
need oxaloacetate
Energy Yields from Beta Oxidation of Fatty Acids
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
why is conversation of FAs to ketone bodies critical?
creates a water-soluble oxidative fuel out of one that is only lipid soluble
ketone bodes are utilized by:
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)
Ketogenesis occurs where?
only in the liver
ketone bodies
acetoacetate and beta-hydroxybutyrate

organic acids, can cause acidosis if they accumulate in excess in plasma
under what conditions are ketone bodies produced?
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
in the absence of glucose acetyl CoA is disposed via pathway in LIVER that generates:
ketone bodies (acetoacetate and beta-hydroxybutyrate)

some acetone also formed (by spontaneous decarboxylation)
fate of acetoacetate and beta hydroxybuyrate in non-hepatic tissues:
reconverted to acetoacetyl-CoA, which is then converted to acetyl CoA for combustion in the TCA cycle

MITOCHONDRIA ARE REQUIRED FOR KETONE OXIDATION
products of Ketogenesis (and destination)
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
how can one detect ketogenesis
breathe smells of acetone

ketones in urine
why can't glucose be made from Fatty Acids
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
If No glucose is ingested:
Insulin levels:
Rate of FA synthesis:
Metabolism of FA:
Insulin levels: LOW
Rate of FA synthesis: LOW
Metabolism of FA: INCREASED