Metabolism Lecture 15
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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) - 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