(Biohemija metabolizma: školska 2019/2020.)

Metabolizam lipida

docent dr Milan R. Nikolić (mnikolic@chem.bg.ac.rs)

Chapter 20: Lipid metabolism (p. 657-711)

• Oksidacija masnih kiselina

• Ketonska tela

• Biosinteza masnih kiselina

• Principi biosinteze

triacilglicerola, fosfolipida I

holesterola

• Principi regulacije metabolizma lipida

http://lipidlibrary.aocs.org/

Ispitna pitanja:

Structures of the most important lipids

Obnovite iz Hemije prirodnih proizvoda osnovna fizičko-hemijska svojstva lipida!

4 major physiological roles:

Note: double bonds when present are cis and unconjugated.

•components of phospho-lipids and glycolipids

•fuel and storage

(triacylglycerols)

•covalent attachment to

proteins, protein targeting

•hormones and intracellular

messengers

Fatty acids

Zbog čega su kod životinja

masne kiseline depoi

metaboličke energije?

Phospholipids (PLs) = Biological membranes

Triacylglycerols (TGs) = Energy source

•Eat foods rich in fats (90% TGs)

• Fats provide about 6 times the energy/mass of carbohydrates

• Stored in an anhydrous state; C-atoms have low oxidation states

TGs: stored in adipose cells, the major form of metabolic energy storage in humans

NB: Inherent hydrophobicity

It is an important component of cell membranes (helps maintain integrity and fluidity)

It helps in the digestion/absorption of lipids (needed for the synthesis of bile salts)

It is a key component in the building of hormones (estrogen, progesterone, testosterone, adrenal corticosteroids)

Cholesterol (Ch) = essential to life

Widly distributed in the body especially in the liver, bile, blood, brain tissue, kidneys, adrenal glands and myelin sheaths of nerve fibers.

https://medlineplus.gov/cholesterol.html

Water-insoluble lipids must be bound to lipoproteins,

specialized lipid-carrying particles

Lipoprotein is the globular micelle-like particle: complex of

triacylglycerols and cholesterol with apolipoproteins and phospholipids

Lipoproteins = Transport lipids

Lipoproteins

Chilomicrons (CM) Produced by the intenstinum (apo B48)

Transports exogenous lipids (triacylglycerols) to the cells

Very-low-density lipoprotein (VLDL) Produced by the liver (apo B100)

Transports endogenous lipids (triacylglycerols) to the cells

Low-density lipoprotein (LDL) Transports endogenous cholesterol to the cells (apo B100)

Also known as “bad cholesterol”

High-density lipoprotein (HDL) Responsible for “recycling” of cholesterol (apo A1)

Also known as “good cholesterol”

(NB: Structural heterogeneity)

Apo(lipo)proteins: carriers, enzyme cofactors, receptor ligands, and lipid transfer

carriers that regulate the metabolism of lipoproteins and their uptake in tissues.

Receptor-mediated endocytosis of LDLs deliver cholesterol to the cells

Nobel Prize in Physiology or Medicine (1985)

Cholesterol and atherosclerosis

HDL particles remove cholesterol from peripheral tissues to liver

HDL are assembled in the plasma from components largely obtained through the degradation of other lipoproteins, but cholesterol from cell-surface membranes. The cholesterol is converted to cholesteryl esters by the HDL-associated enzyme lecithin-cholesterol acyltransferase (LCAT), activated by apoA-I. The liver is the only organ capable of disposing of significant quantities of cholesterol by its conversion to bile acids. HDL particle binds to a cell-surface receptor named SR-BI (for scavenger receptor class B type I) and selectively transfers its component lipids to the cell. The lipid-depleted HDL particle then dissociates from the cell and re-enters the circulation.

Processing of dietary lipids in vertebrates

NB: Fiziologija!

Mobilization of stored triacylglycerols

•Hormones (epinephrine, glucagon) secreted due to low blood glucose levels activate adenylyl cyclase.

•cAMP dependent protein kinase phosphorylates perilipin.

•Phosphorylated perilipin recruits hormone-sensitive lipase (HSL) to lipid droplet surface.

•HSL hydrolyzes triacylglycerols to free fatty acids.

• Free fatty acids are transported to bloodstream.

• The complex of up to 10 fatty acids per serum albumin is transported to the target tissues.

~95% of the biologically available energy of triacylglycerols is due to the three fatty acid chains. Only 5% is due to the glycerol moiety.

Overview of TGs/cholesterol transport in humans

Peripheral tissues: FAs catabolism or storage

The utilization of (stored) triacylglycerols requires three stages of processing

1. Hormone-sensitive lipase of adipose tissue liberates fatty acids,

that are carried in the blood by serum albumin.

2. At the consuming tissues, fatty acids are activated and

transported into the mitochondrion for degradation.

3. In the mitochondrion, fatty acids are broken down in a step-

wise fashion to form acetyl-CoA, which is used in the TCA cycle.

NB: In plants FA oxidation occurs exclusively in the peroxisomes and glyoxysomes!

(Apoprotein-sensitive lipoprotein lipase liberates FAs from CM and VLDL particles in the capillaries of (skeletal) muscle and adipose tissue)

Glycerol from the breakdown of dietary and endogenous triacylglycerols

is transported to the liver and used in glycolysis and gluconeogenesis.

Fatty acids released from adipose tissue is carried in the bloodstream by serum albumin.

Kidneys

Fatty acid (FA) oxidation

Fatty acids are activated by their attachment to coenzyme A

Carnitine carries acyl groups across the mitochondrial membrane

Oxidation degrades fatty acids to acetyl-CoA

Oxidation of unsaturated fatty acids requires additional enzymes

Oxidation of odd-chain fatty acids yields propionyl-CoA

Peroxisomal oxidation differs from mitochondrial oxidation

FAs are catabolized by an oxidative process that releases free energy

*Minimum za ispit!

Activation of fatty acids

Family of at least three acyl-CoA synthetases (thiokinases) differing in their chain-length specificities. These enzymes are associated with either the endoplasmic reticulum or the outer mitochondrial membrane.

NB: in the cell cytosol

Requires Energy

* Fatty acyl-CoA esters are transported into the mitochondria or used

to synthesize membrane lipids (cytosol).

Activated fatty acids are transported into the mitochondrion

A long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane

(trans-esterification)

Fatty acyl-carnitine enters the matrix via the acyl-carnitine/carnitine antiporter.

Complete fatty acids oxidation

Stage 1: Fatty acids are sequentially

converted to acetyl-CoA

through the β-oxidation of

fatty acyl-CoA.

Stage 2: Acetyl groups are oxidized to

CO2 by the citric acid cycle.

Stage 3: Electrons derived from

oxidations in stages 1 and 2 enter the respiratory chain.

Mitochondria

β-Oxidation of FAs

1. Formation of a trans-α,β double

bond by acyl-CoA dehydrogenase - form FADH2

2. Hydration of the double bond by

enoyl-CoA hydratase

3. Formation of β-hydroxyacyl-CoA by

3-L-hydroxyacyl-CoA dehydrogenase - produces β-keto group and NADH

4. Thiolysis reaction with CoA, by β-

ketoacyl-CoA thiolase

- produces Acetyl-CoA and a shortened

(2C) fatty acyl-CoA

Steps 1-3 resemble (chemically) the CAC reactions that convert succinate to oxaloacetate.

Ponavljajući sled od četiri reakcije

Strategija: kreirati karbonilnu grupu na β-C atomu!

Reverse Claisen condensation

Degradation (β-oxidation) of FAs Occurs in the mitochondrial matrix in 4 (repeated) reactions

(α4β4)

* Long-chain (LC) enoyl-CoAs are converted to acetyl-CoA and a shorter Acyl-CoA by mitochondrial trifunctional enzyme.

*

(Four) ADs is linked to the electron-transport chain.

*

(multifunctional enzyme + multienzyme complex)

Summary of FAs β-oxidation

Pathway operates in

a repetitive fashion

(removing C2 units)

(lokalazacija puta)

(hemijska logika puta)

Fatty acid oxidation is highly exergonic

Each round of oxidation produces ___ NADH, ___ FADH2, and __ acetyl-CoA. Oxidation of acetyl-CoA via the citric acid cycle generates an additional ___ FADH2 and ___ NADH, which are re-oxidized through

oxidative phosphorylation to form ATP.

Oxidation of palmitoyl-CoA (C__ fatty acid) involves ___ rounds of oxidation, yielding __ FADH2, __ NADH, and ___ acetyl-CoA. Oxidation

of the __ acetyl-CoA, in turn, yields __ GTP, __ NADH, and __ FADH2.

Since oxidative phosphorylation of the ___ NADH molecules yields ___ ATP and that of the ___ FADH2 yields ___ ATP, subtracting the ___ ATP equivalents required for fatty acyl-CoA formation, the oxidation of one palmitate molecule has a net yield of ___ ATP.

The function of fatty acid oxidation is to generate metabolic energy

Acetyl-CoA is further oxidized in the Citric Acid Cycle!

The complete oxidation of palmitate yields ~106 molecules of ATP

There will be 7 turns of the cycle, with the final turn generating 2 acetyl~CoA

Palmitoyl~CoA + 7 FAD + 7 NAD+ + 7 CoA → 8 acetyl~CoA + 7 FADH2 + 7 NADH + 7 H+

7 NADH x 2.5 ATP/NADH --------------> 17.5 ATP

7 FADH2 x 1.5 ATP/FADH2 -------------> 10.5 ATP

8 acetyl~CoA x 10ATP/acetyl~CoA ------> 80 ATP

Total ------------------------> 108 ATP

Activation of palmitate --------------------> -2 ATP

Yield ------------------------> 106 ATP

Assuming that mitochondrial oxidative phosphorylation produces 1.5 ATP per FADH2 and 2.5 ATP per NADH.

Problems in the oxidation of unsaturated fatty acids

Oxidation requires two additional reaction

Poor substrate for enoyl-CoA hydratase

Not a substrate for

enoyl-CoA hydratase

Linolna kiselina

Three isomerases and a reductase permit oxidation of unsaturated FAs

The oxidation of unsaturated fatty acids

Linolenska kiselina

Plants and marine organisms synthesize FAs with an odd number of carbon atoms*

(The final round of oxidation yields propionyl-CoA, which is converted to succinyl-CoA for entry into the citric acid cycle)

Oxidation of odd-chain FAs yields propionyl-CoA

Formation of succinyl~CoA involves addition of a one-carbon unit and rearrangement of the carbon skeleton

(Ile, Met, Val)

* Cattle (ruminant animals) form large amounts of propionate in the rumen.

B12

B7

Methylmalonyl-CoA mutase uses a 5-deoxyadenosylcobalamin prosthetic

group (coenzyme B12).

It must first be converted to pyruvate!!!

• Malate oxidative decarboxylation to pyruvate and CO2 by malic enzyme.

• Pyruvate is completely oxidized via pyruvate dehydrogenase and the citric acid cycle.

Succinyl~CoA → succinate → fumarate → malate

to cytosol

NB: C4 cycle of photosynthesis!

Succinyl-CoA is not directly consumed by the citric acid cycle

Shortens very long chain (VLC; 22C atoms)

and branched FAs*, which are then fully

degraded by the mitochondrial pathway.

VLCFAs are transported into the peroxisomes by a mechanism that does not require carnitine.

Peroxisomal FAs β-oxidation

The process consists of four steps:

1) dehydrogenation

2) addition of H2O

3) oxidation of β-hydroxyacyl-CoA

4) thiolytic cleavage by CoA

Flavoprotein acyl-CoA oxidase passes electrons directly to O2 producing H2O2

- H2O2 is immediately cleaved by catalase

* If the branch is at odd-number carbons undergo α-oxidation.

Different abilities of tissues to utilise various metabolic fuels

Brain: 100-145 g/day of Glc (FAs cannot pass through the blood-brain barrier)

NB: Nabrojite i predstavite hemijskim formulama

najvažnija metabolička goriva u organizmu čoveka.

• Acetyl-CoA can be oxidized via the citric acid cycle as long as sufficient OAA is present.

• Between meals or during fasting, gluconeogenesis in the liver produces glucose for the peripheral tissues. This diverts OAA from the citric acid cycle… the cycle cannot turn.

• The liver then synthesizes “ketone bodies” (ketogenesis) which essentially serve as the water-soluble equivalent of acetyl-CoA (FAs).

• The skeletal muscle, heart muscle, kidney, and brain switch from using glucose as the main energy source to using ketone bodies during prolonged fasting, to spare glucose and muscle proteins. Heart muscle/renal cortex use acetoacetate in preference to glucose.

• Abnormally high levels of ketone bodies are found in the blood of untreated diabetics.

NB: In mammals, there is no pathway for the formation of glucose from acetyl-CoA.

“Fat burns in the flame of carbohydrates”

Ketone bodies: An alternative fuel (Under conditions of carbohydrate deficiency)

Ketone bodies allow continued oxidation of fatty acids in the

liver when acetyl-CoA is not being oxidized in the citric acid cycle!

Ketogenesis (liver mitochondria)

Step 1: Formation of acetoacetate → condensation of to acetyl-CoA

Step 2: β-hydroxy-β-methylglutaryl-CoA

(HMG-CoA) synthase catalyses the

condensation of acetyl-CoA

with acetoacetyl-CoA

Step 3: β-hydroxy-β-methylglutaryl-CoA

is cleaved by HMG-CoA lyase to form

acetyl-CoA and Acetoacetate

Step 4a: Acetoacetate is decarboxy-

lated to form Acetone

Step 4b: Acetoacetate is reduced to D-

β-hydroxybutyrate. → the DH is specific for the D form

Only in liver!

*

* spontanous: waste product (lung, urine)

D-β-hydroxybutyrate as a fuel

The liver releases acetoacetate

and β-hydroxybutyrate, which are

carried by the bloodstream to the

peripheral tissues!

• In extrahepatic tissue D-β-

hydroxybutyrate is oxidized

to acetoacetate.

• Acetoacetate is activated

to acetoacetyl-CoA by

transfer from succinyl-CoA.

• Cleavage by thiolase

yields two acetyl-CoAs

→ citric acid cycle

Liver lacks this enzyme!

(Energy source for heart and skeletal muscle; the

main sourse of energy for the brain in starvation)

Cholesterol is synthesized from acetyl-CoA in three stages

1. Synthesis of activated isoprene unit,

isopentenyl pyrophosphate (IPP).

2. Condensation of 6 molecule of IPP

to form squalene.

3. Squalene cyclizes and the tetracyclic

product is converted to cholesterol.

Complex pathways of over 40 cytosolic and membrane-bound enzymes.

Normal mammalian cells tightly

regulate cholesterol synthesis to

maintain cellular cholesterol

levels within narrow limits.

Fatty acid biosynthesis is different from the β-oxidation degradation pathway

Differences occur in: (1) cellular location, (2) acyl group carrier, (3) electron

acceptor/donor, (4) stereochemistry of the hydration/dehydration reaction,

and (5) the form in which C2 units are produced/donated

FA biosynthesis occurs through condensation of C2 units, the reverse of the β-oxidation process!

The design strategy for de novo fatty acid biosynthesis

• Fatty acids are constructed by the addition of two carbon

units derived from acetyl-CoA.

• The acetate units are activated by the formation of malonyl-

CoA at the expense of ATP.

• The driving force for the addition of two carbon units to the

growing chain is the decarboxylation of malonyl-CoA.

• The chain elongation stops at palmitoyl-CoA.

• Other enzymes add double bonds or additional carbon

atom to the carbon chain.

• In mammals occurs primarily in the liver and adipose tissues;

in mammary glands during lactation.

FA biosynthesis in the cytosol requires a sufficient concentration of NADPH and acetyl-CoA*

* NADPH is generated in the cytosol by the pentose phosphate pathway, and by the malic enzyme;

* 3 principle ways of producing acetyl-CoA in the cytosol of the cell (AAs degradation, citrate "from" either FA oxidation or glycolysis)

Tricarboxylate transport system for transfer of

acetyl~CoA from mitochondrion to cytosol

Citrate carries acetyl groups from the mitochondrion to the cytosol for fatty acid synthesis

• Acetyl-CoA is generated the oxidation of FAs and by pyruvate dehydrogenase.

• Excess acetyl~CoA is shipped to the cytosol for storage as fat.

• Citrate is passed to the cytosol.

• ATP-citrate lyase regenerates the acetyl-CoA and OAA in cytosol.

• Malic enzyme produces the NADPH that may be used in fatty acid synthesis.

Mitochondrial acetyl-CoA must

be transported into the cytosol

What is the energetic cost of this cycle?

The formation of malonyl-CoA

The acetyl CoA molecules need to be activated for fatty acid biosynthesis

• Acetyl CoA is carboxylated to form

malonyl CoA by acetyl-CoA

carboxylase (ACC), which is a biotin

containing enzyme.

• The carboxylation reaction is

irreversible and is the first committed

step of fatty acid biosynthesis.

• The mechanism of this carboxylase is

the same as pyruvate carboxylase

and propionyl CoA carboxylase.

- ATP is used to activate bicarbonate in the form of carboxyphosphate which leads to the carboxylation of biotin.

- The activated CO2 group is transferred to acetyl-CoA to form malonyl CoA.

A single polypeptide chain has all three functions.

Acetyl-CoA carboxylase

As the first committed step of FA biosynthesis, acetyl-CoA carboxylase is allosterically regulated

• The final product of fatty acid biosynthesis is palmitoyl CoA. There is an allosteric binding site for palmitoyl-

CoA which shifts the equilibrium toward the inactive enzyme.

• Citrate, a precursor for acetyl CoA formation, is an allosteric activator of this enzyme. It binds to an allosteric

binding site shifting the equilibrium towards the active enzyme.

• The regulatory effects of citrate and palmitoyl CoA are modulated by the phosphorylation state of ACC.

In animals, ACC is a filamentous polymer composed of 230 kD protomers

Acyl carrier protein (ACP) The intermediates (the growing chain) during FA biosynthesis

are linked to an acyl carrier protein!

AMP

The ACP is similar to coenzyme A (phosphopantetheine prosthetic group)

In mammals, acyl carrier protein is part of fatty acid synthase.

Fatty Acid Synthesis

Step 1: Loading – transferring acetyl- and malonyl- groups from CoA to ACP

Step 2: Condensation – transferring 2 carbon unit from malonyl-ACP to acetyl-ACP to form 2 carbon keto-acyl-ACP

Step 3: Reduction – conversion of keto-acyl-ACP to hydroxyacyl-ACP (uses NADPH)

Step 4: Dehydration – Elimination of H2O to form Enoyl-ACP

Step 5: Reduction – Reduce double bond to form 4 carbon fully saturated acyl-ACP

The Fatty Acid Synthase (FAS) multienzyme complex of eukaryotes

Animal FAS complexes are dimers of αβ subunits

• The α-subunits contain the β-

ketoacyl-ACP synthase domain and the β-ketoacyl

reductase domain.

• The β-subunit contains the

acetyl transferase domain,

the malonyl transferase domain, the β-hydroxyacyl

dehydro-genase domain and

the enoyl reductase domain.

Catalyzes seven reactions!

Activation

Elongation

Termination

Elongation cycle of fatty acid biosynthesis

… begins with the formation of acetyl-ACP and malonyl-ACP

• Before fatty acid biosynthesis begins, fatty acid synthetase must be primed with acetyl-CoA.

- Acetyl transacylase (AT) and malonyl transacylase (MT) catalyzes the reactions.

AT will also catalyze the following reaction at a much slower rate:

Propionyl-CoA + ACP → Propionyl-ACP + CoA

Reaction cycle for FA biosynthesis by FAS

NB: The fatty acid grows from its thioester end

The first step of the fatty acid synthase reaction is the formation of acetyl-O-enzyme intermediate between an acetyl group of acetyl CoA and an active site serine residue of the acetyl transferase domain, and malonyl-O-enzyme intermediate between malonyl CoA and an active site serine residue of the malonyl transferase domain.

The next step is the transfer of the acetyl group to the sulfhydryl of the acyl carrier protein (ACP). This acyl group is then transferred one more time to a cysteine residue of β-ketoacyl-ACP synthase. This frees the acyl carrier protein to acquire the malonyl group from the malonyl transferase.

The next step is the condensation reaction in which decarboxylation of the malonyl-ACP generates a highly reactive nucleophile that attacks the carbonyl of acetyl-S-KSase.

The next three steps are the reduction of the carbonyl to the alcohol, the dehydration and the reduction of the alkene to form saturated butyryl-ACP. A second malonyl group is transferred from malonyl CoA to the active site serine of malonyl transferase. The butyryl-ACP is then transferred to the cysteine residue of KSase. This frees the acyl carrier protein to acquire the malonyl group from the malonyl transferase.

The next step is the condensation reaction in which decarboxylation of the malonyl-ACP generates a highly reactive nucleophile that attacks the carbonyl of butyryl-S-KSase.

This cycle continues until palmitoyl ACP is formed. The thioester bond is hydrolyzed by thioesterase (TE) to form palmitate.

Palmitate is the primary product of fatty acid synthase*

* FAs with shorter chains can be generated by releasing the FA before reaching 16 carbons of length.

Mechanism of C-C bond formation in fatty acid biosynthesis

Notes:

The CO2 that was added in the ACC reaction

is lost as CO2 and does not appear in the fatty acid.

Loss of CO2 results in resonance-stabilized carbanion!

The formation of a carbon-carbon bond

is an endergonic process requiring an

activated precursor.

Malonyl-ACP is a β-keto ester whose exergonic

decarboxylation yields the acetyl-ACP carbanion.

The free energy required is supplied by

the ATP hydrolysis in the ACC reaction.

FAS is overexpressed in certain breast

cancers: FAS inhibitors may be useful drugs

In mice, inhibitors of KS lead to remarkable

weight loss.

The two halves of fatty acid synthase operate in concert

The two subunits of FAS form an

asymmetric X with two reaction chambers:

• the lower portion of the X contains

the enzyme’s two condensing activities; • the upper portion of the X contains the

enzyme’s carbon modifying activities.

Because FAS is a dimer, two fatty acids can

be synthesized simultaneously.

Notes:

In well-nourished individuals, FA synthesis proceed at a low rate!

A molecule of sintetized palmitate costs ~136 ATP

8 acetyl~CoA @ 10 ATP/acetyl~CoA 80 ATP

14 NADPH @ 3.5 ATP/NADPH 49 ATP

7 ATP 7 ATP

Total: 136 ATP

The overall reaction is shown below:

The overall stoichiometry for palmitate biosynthesis:

The camel‘s hump = a fat depot

8 Acetyl-CoA + 7 ATP + 14 NADPH + 7 H+ →

Palmitate + 14 NADP+ + 7 ADP + 7 Pi + 8 CoA+ 6 H2O

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+

→ Palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O

The formation of 7 malonyl CoA requires:

7 Acetyl-CoA + 7 CO2 + 7 ATP → 7 Malonyl-CoA + 7 ADP + 7 Pi + 7 H+

The elongation and desaturation of fatty acids are accomplished by additional enzyme systems

• Elongases are present on the cytosolic face

of the endoplasmatic reticulum and in the mitochondrion.

• Desaturases are mainly in the ER membrane.

Mammals cannot introduce double bonds beyond C9,

thus linoleic and linolenic acids are essential FAs.

Mitochondrial FA elongation (the reverse of fatty acid oxidation)

▬ except that the final reaction employs NADPH rather than FADH2 as its redox coenzyme!

Elongation in the ER: the successive condensations of

malonyl-CoA with acyl-CoA, each followed by NADPH-

dependent reductions similar to those catalyzed by FAS

(but FA is elongated as its CoA, not ACP derivative).

Unsaturated fatty acids are produced by terminal desaturases (Mammals: Δ9-, Δ6-, Δ5-, and Δ4-fatty acyl-CoA desaturases)

Synthesis of Triacylglycerols

The acyltransferases are not completely specific for particular fatty acyl-CoAs.

ER, peroxisomes

ER, mitochondrion

In ER membrane, these 2 form a complex

OAA (glyceroneogenesis)

Glc (glycolysis)

A summary of lipid metabolism

The flux of material in the direction of triacylglycerol synthesis or triacylglycerol

degradation depends on the metabolic energy needs of the organism and the

need for synthesis of other compounds, such as membrane lipids and cholesterol.

(Central function of lipids in energy metabolism)

The balance between insulin (fed state) & glucagon (fasted state) secretion

Holds metabolism "on the line", promoting homeostasis (a stable inner metabolic milieu)

NB: The glucagon:insulin ratio determines the rate and direction of FAs metabolism!

Regulation of fatty acid metabolism Fatty acid metabolism is coordinated

with other aspects of metabolism.

(hormones and cellular factors)

(As for glycogen metabolism) Hormonally

regulated by pancreatic α- and β-cells, which

sense metabolic status and secrete glucagon

and insulin, respectively.

The simultaneous synthesis and oxidation

of fatty acids in liver cells is prevented.

Malonyl~CoA inhibits carnitine palmitoyl

transferase I.

Long term regulation-synthesis of ACC

adipose lipoprotein lipase, and FAS

stimulated by insulin, inhibited by

glucagon, epinephrine.

A diet high in polyunsaturated FA also

causes decreased FAS, ACC.

Metabolites for energy production: TAGs, FAs, ketone bodies, AAs,

lactate, and glucose.

NB: short-term (substrate availability, allostery, phosphorylation) vs. long-term regulation (gene expression)

Synthesis of phospholipids

NB: Fatty acids are the precursors not just of triacylglycerols

but a variety of other component, incl. membrane lipids and signaling molecules.

(A) Glycerophospholipids are built from intermediates of TAGs synthesis (1,2-diacylglycerol and phosphatidic acid)

(B) Sphingolipids are built from palmitoyl-CoA and serine

Why are there so many different phospholipids?

Phospholipid composition dictates membrane behavior.

Distribution of membrane lipids

Animals major components are PE, PS, PC & cholesterol cell membranes of the central nervous system

contain additional lipids (sphingomyelin, myelin, cerebrosides, gangliosides...)

Plants PE and PC predominate

PI and PG are present as well cholesterol is absent but replaced by phytosterols

Bacteria major components are PE and PG

PC is rarely present, sterols are absent

Biosynthesis of PC (lecithin) and PE & PS (cephalin)

Biosynthesis of PI (important in cell signaling)

Enzymes that synthesize phosphatidic acids have

a general preference for saturated fatty acids at

C1 and for unsaturated fatty acids at C2.

Biosynthesis of ceramide (N-acylsphingosine)

Phosphatidylcholine donates its phosphocholine group to C1-OH group of ceramide.

• Cerebrosides are ceramide monosaccharides,

whereas gangliosides are sialic acid-containing

ceramide oligosaccharides. These lipids are

synthesized by attaching carbohydrate units to

the C1-OH group of ceramide.