Lipid Metabolism Flashcards
Lipids
- Fatty compounds that perform a
variety of functions in your body. - Lipids are fatty, waxy, or oily
compounds that are soluble in
organic solvents and insoluble in
polar solvents such as water. Lipids
include: - Fats and oils (triglycerides)
- Phospholipids
- Waxes
- Steroids
Fatty Acids
- Essential fuel and major energy source
- A lot of the fat used by the body comes
from diet - You can also synthesise fatty acids from
Acetyl CoA - Have molecular formular R-COOH i.e. something carry a
carboxylic acid group - Therefore, fatty acids are weak acids
- Due to the average pKa value of fatty acids (~4.5) at physiological
pH the equilibrium position lies to the right of the equation. - Fatty acids exist in their anionic form under physiological
conditions. - This has the suffix “–ate” rather than “–ic acid”
- Terms often used synonymously incorrectly
Required for lipogenesis:
synthesis of TAG, an energy
dense storage molecule - Synthesised from Acetyl
CoA - In fed state, Acetyl CoA is
abundant → stored in
adipose tissue as TAG
OR - FA released into the blood
stream from TAG by
lipolysis when there is a
need for energy
Saturated vs unsaturated FA
Unsaturated = double bond
at some location in the
hydrocarbon tail
* Saturated = no double bonds,
no opportunity for new bonds
to be formed
* Polyunsaturated = more than
one double bond
* Monounsaturated = one
double bond
Cis and trans configuration of the C=C double bond
- Double bonds may be in 2 stereoisomeric
configurations - C=C double bond has significant
consequences for the molecular properties
(structure, chemical characteristics) - Cis = sharp bend in the hydrocarbon chain
- Trans = no sharp bend
- Most natural FA possess C=C bonds in the
cis configuration
Triacylglycerides
- AKA triglyceride
- Triacylglycerol is the major form of
dietary lipid in fats and oils - Triacylglycerol is composed of three
fatty acids esterified to a glycerol
Lipid Digestion
- Mouth: lingual lipases,
which are secreted by
glands in the tongue to
begin the process of
digesting triglycerides - Stomach is also the major
site for the emulsification
of dietary fat and fat-
soluble vitamins
Absorption
- FA + MAG absorbed by enterocyte.
- Assembled in chylomicron.
- Chylomicron travels to blood via
lymphatic system - Chylomicron acquires CII
- LPL activates after contact with CII.
- TAG hydrolysed to FFA and glycerol
and delivered to cells - Chylomicron returns CII to HDL
- Chylomicron remnants endocytosed
by hepatocytes
Lipid Catabolism
- TAG stores in adipose tissue are a major fuel reserve
- Easily mobilised for exercise or starvation
- Lipolysis (splitting TAG into FA and glycerol)
- FA ‘activation’ (molecular modification of liberated
FAs necessary to obtain access to the mitochondria)
- FA ‘activation’ (molecular modification of liberated
- FA entry into mitochondria (from the cytoplasm)
- β-oxidation (oxidation, releasing energy)
1) Lipolysis
- Cytosol of adipose cells
- Hydrolysis of TAG by lipase
- Produces glycerol and free fatty acids
- Hormone sensitive lipase (HSL) hydrolyses TAG→ MAG
- MAG-specific lipase removes remaining fatty acid
- Glycerol transported to liver to make TAG or be
converted to intermediate for gluconeogenesis - FFA either re-esterified to TAG in adipocyte or
transported in blood for oxidation
2) Activation of Fatty Acids
Fatty acyl CoA synthetase
(thiokinase) activates fatty
acids by attaching them to CoA
* Requires ATP
* Fatty acids are non-polar and
would diffuse out of cells.
* Addition of CoA traps the fatty
acid inside
3) Transport to Mitochondria
Fatty acids enter
mitochondrial matrix via
carnitine shuttle
4) β-oxidation
- FA catabolism generates
FADH2 and NADH+H+ and
releases acetyl CoA. - Acetyl CoA enters the TCA
cycle for oxidation and
reducing equivalents can
undergo oxidative
phosphorylation to release
energy - Each cycle reduces chain by 2
carbons (Acetyl CoA) - 1) Oxidation
- 2) Hydration
- 3) Oxidation by NAD+
- 4) Thiolytic cleavage by CoA
- Repeat cycle until complete
oxidation
TAG Biosynthesis
- Bulk of human energy from
carbohydrates - Storage as glycogen is limited
- Conversion from carbohydrate to
fat is required - Acetyl CoA from Glycolysis is
incorporated into new fatty acid
molecules. - Then FA esterified to TAG for
storage in adipose tissue - Occurs in cytoplasm of
adipocytes, liver, kidney and
lactating mammary gland
Fatty Acid Biosynthesis
STEPS
* 1) Transport of acetyl CoA to the cytoplasm, where the synthetic
enzymes are located
* 2) Activation: synthesis of malonyl CoA and localising at fatty acid
synthase
* 3) Sequence of condensation, reduction, dehydration and a
second reduction
* 4) Addition of a 2-carbon unit (derived from another malonyl coA)
* 5) Repeat 3 & 4 – No of repeats determines the length
1) Transport of acetyl CoA from mitochondria
to cytoplasm
- Mechanism known as the citrate shuttle or
pyruvate-malate cycle - Acetyl CoA condenses with oxaloacetate
to form citrate - Citrate exported from matrix to cytoplasm
in exchange for malate - Citrate reacts with ATP and CoA to form
oxaloacetate and acetyl CoA - Oxaloacetate is reduced to malate
- Malate decarboxylated to pyruvate
- Pyruvate re-enters mitochondria where is
regenerates oxaloacetate
2) Synthesis of malonyl CoA
- Irreversible rate limiting step of FA
synthesis - Carboxylation of acetyl coA to
malonyl CoA - Acyl carrier protein (ACP) is a
component of fatty acid synthase
(FAS) - ACP accepts acyl groups. 2 ACP
required as FAS is a homodimer
3) condensation, reduction, dehydration and a second reduction
Condensation
* ACP-anchored acetyl group is
cleaved off and transferred to
the protruding end of the
malonyl group
* This transfer displaces the
carboxyl group, liberating CO2.
* Results in a saturated four-
carbon chain, still attached to
the ACP. This forms the basic
skeleton of an FA.
Malonyl-ACP
Acyl-ACP
- Keto group at C3 (R-C(=O)-R’) reduced to
alcohol group (-OH) - Double bond introduced between C2 &
C3 releasing H20 - Double bond removed by saturation of
C2 and C3 with H
4) Addition of a 2-carbon unit
- 4C chain condenses with malonyl CoA to form a 6C chain.and repeat until 16C palmitate
Each repeat requires a malonyl CoA
molecule
Lipogenesis: TAG Synthesis
3 stages
1. Formation of glycerol-3-phosphate
* Glycerol is phosphorylated at C3 by glycerol kinase using
ATP as the phosphate donor,
* Dihydroxyacetone phosphate (DHAP) is reduced by
glycerol-3-phosphate dehydrogenase.
2. FA activation.
* FA attach to CoA. Fatty acyl-CoA synthetase performs
this reaction.
3. Esterification of glycerol-2-phosphate
* The three activated FAs are esterified to glycerol-3-
phosphate in stages.
Sugar
Carbohydrate containing foods are broken down by the body to glucose.
Glucose is then used for energy. Excess glucose can be converted to
triglycerides for storage in adipocyte
Cholesterol
Cholesterol is a sterol/lipid
We get some from our diet
We synthesis some
Mostly associated with
CVD
Cholesterol Absorption
- Free cholesterol is more readily incorporated into bile acid micelle
- Cholesterol absorbed 29.0-80.1%
- Free cholesterol absorbed by clathrin-mediated endocytosis via NCP1L1
- Acetyl CoA:acetyltransferase 2 (ACAT2) converts FC to CE
- Microsomal triglyceride transfer protein (MTP) shuttles CE for incorporation
into nascent chylomicron
Hepatic Absorption of
Chylomicron Remnants
- Chylomicron acquires apo C-II and E from HDL
converting nascent chylomicron to mature chylomicron - Within tissues, apo C-II activate lipoprotein lactase
(LPL) found on the capillary endothelium, catalysing the
hydrolysis of TAG - Chylomicron remnant returns apo C-II to HDL
- Apo B-48 and apo E recognised by hepatic LDLr and low
density lipoprotein receptor-related protein (LRP),
inducing uptake of chylomicron remnant
