LIPID DIGESTION AND
METABOLISM
Part 1: Lipid Characteristics
Lipid = a compound that is insoluble in water, but soluble
in an organic solvent (e.g., ether, benzene, acetone,
chloroform)
lipid is synonymous with fat, but also includes
phospholipids, sterols, etc.
Chemical structure: glycerol + fatty acids
Lipid Molecule
Nutritional Uses of Lipids
We already know that lipids are concentrated sources of
energy (9.45 kcal/g)
Other functions:
Provide means whereby fat-soluble nutrients (e.g., sterols,
vitamins) can be absorbed by the body
Structural element of cell, subcellular components
Components of hormones and precursors for prostaglandin
synthesis
Lipid Classes
Simple: FAs esterified with glycerol
Compound: same as simple, but with other compounds also attached
Phospholipids: fats containing phosphoric acid and nitrogen (lecithin)
Glycolipids: FAs compounded with CHO, but no N
Derived lipids: substances from the above derived by hydrolysis
Sterols: large molecular wt. alcohols found in nature and combined
w/FAs (e.g., cholesterol)
Saturated vs. Unsaturated Fatty Acids
Saturated: the SFAs of a lipid have no double bonds between
carbons in chain
Polyunsaturated: more than one double bond in the chain
Most common polyunsaturated fats contain the polyunsaturated fatty
acids (PUFAs) oleic, linoleic and linolenic acid
unsaturated fats have lower melting points
stearic (SFA) melts at 70oC, oleic (PUFA) at 26oC
Fatty Acids Commonly Found in Lipids
o
Sat. Fatty Acids Formula Melting Point ( C)
Butyric C4H8O2 Liquid
Palmitic C16H22O2 63
Stearic C18H36O2 70
Unsat. Fatty Acids Formula Melting Point (oC)
Oleic C18H34O2 Liquid
Linoleic C18H32O2 Liquid
Linolenic C18H30O2 Liquid
Saturated vs. Unsaturated Fats
Saturated fats tightly packed, clog arteries as
atherosclerosis
Because of double bonds, polyunsaturated fats do not
pack well -- like building a wall with bricks (sat.) vs.
irregular-shaped objects (unsat.)
Plant fats are much higher in PUFAs than animal fats
Saturated vs. Unsaturated FAs Plant vs.
Animal Fat
corn soy tallow lard
Sat. FAs
Myristic 3
Palmitic 7.0 8.5 27 32.2
Stearic 2.4 3.5 21 7.8
Unsat. FAs
Oleic 45.6 17 40 48
Linoleic 45.0 54.4 2 11
Linolenic 7.1 0.5 0.6
Arachid.
Lipid Digestion, Absorption and
Transport
Major form of energy:
triacylglycerol/fat/triglycerides
90% of dietary lipid
Oxidized to CO2 and H2O
6 times more energy/weight of glycogen
Water insoluble
Digestion at lipid/water interface
Lipid Digestion, Absorption and
Transport
Major form of energy:
triacylglycerol/fat/triglycerides
Emulsified by bile salts/bile acids in small intestine
Cut at pos 1 and 3 by lipase (triacylglycerol lipase)
TAG -> 1,2-diacylglycerol -> 2 acylglycerol
+ Na+, K+ salts -> fatty acid salts/soap bind to I-FABP
Lipid Digestion/Absorption
Fats serve a structural function in cells, as sources of
energy, and insulation
The poor water solubility of lipids presents a problem
for digestion: substrates are not easily accessible to
digestive enzymes
Lipid Digestion/Absorption
Even if hydrolyzed, the products tend to aggregate to larger
complexes that make poor contact with the cell surface and
arent easily absorbed
To overcome these problems, changes in the physical state of
lipids are connected to chemical changes during digestion
and absorption
Energy Content of Food
Constituents
Lipid Digestion/Absorption
Five different phases:
Hydrolysis of triglycerides (TG) to free fatty acids (FFA) and
monoacylglycerols
Solubilization of FFA and monoacylglycerols by detergents (bile acids)
and transportation from the intestinal lumen toward the cell surface
Uptake of FFA and monoacylglycerols into the cell and re-synthesis to
triglyceride
Packaging of TGs into chylomicrons
Exocytosis of chylomicrons into lymph
Enzymes Involved in Digestion of
Lipids
Lingual lipase: provides a stable interface with aqueous
environment of stomach
Pancreatic lipase: major enzyme affecting triglyceride
hydrolysis
Colipase: protein anchoring lipase to the lipid
Lipid esterase: secreted by pancreas, acts on cholestrol
esters, activated by bile
Phospholipases: cleave phospholipids, activated by trypsin
Mechanism of interfacial
activation of
triacylglycerol lipase in
complex with
procolipase
Pancreas Lipase = TAG lipase
Lipase activation by colipase
Interfacial activation
Activity depends on surface
area
Hydrolysis similar to peptidase
What about Bile???
These are biological detergents synthesized by the liver and secreted into
the intestine
they form the spherical structures (micelles) assisting in absorption
hydrophobic portion (tails of FA) are located to the inside of the micelle,
with heads (hydrophillic portion) to the outside
they move lipids from the intestinal lumen to the cell surface
absorption is by diffusion (complete for FA and monoglycerides, less for
others)
Factors Affecting Absorption of
Lipids
Amount of fat consumed
(fat=digestion=absorption)
Age of subject ( age =
digestion)
Emulsifying agents ( digestion =
absorption)
Factors Affecting Absorption of
Lipids
Chain length of FAs (> 18C = digestibility)
Degree of saturation of FA ( sat =
digestibility)
Overheating and autooxidation
(rancidification (rot) at double bond)
Optimal dietary calcium = optimal FA
absorption (high Ca = absorption)
Lipid Metabolism/Absorption
Short chain FAs are absorbed and enter the portal vein to the liver
Those FAs with more than 10 carbons are resynthesized by the liver to
triglycerides
They are then converted into chylomicrons and pass to the lymphatic
system
Some FAs entering the liver are oxidized for energy, others stored
Blood lipids: 45% P-lipids, 35% triglycerides, 15% cholestrol esters, 5%
free FAs
Lipid
Digestion/Absorption
Lipid
Digestion/Absorption
Lipid transport
Hydrolyzed lipids are absorbed by the intestinal mucosa
Converted back to triglycerides !
Packed into lipoprotein particles, chylomicrons
Released into lymph/blood -> delivered to tissue
Triglyceride made by liver is packaged into VLDL part. ->
Lipid transport
Released into blood
TAG hydrolyzed in periphery by lipoprotein lipase ->
FA uptake but glycerol back transport to liver and kidney
TAG in adipose tissue is mobilized by hormone-sensitive
lipase -> free FA enter blood, bound to serum albumin
Characteristics of Fat Storage
Most of the bodys energy stores are triglycerides
Storage is in adipose, source is dietary or anabolism
(synthesis) from COH or AA carbon skeletons
What happens in obesity?
Adipose can remove FAs from the blood and enzymes
can put them back
Fatty Acid Nomenclature
Nomenclature reflects location of double bonds
Also used are common names (e.g., oleic, stearic, palmitic)
Linoleic is also known as 18:2 n-6
This means the FA is 18 carbons in length, has 2 double bonds,
the first of which is on the 6th carbon
Arachidonic = 20:4 n-6
Essential Fatty Acids
LINOLEIC CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH
18:2 n-6
LINOLENICCH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7COOH
18:3 n-3
EICOSOPENTAENOIC ACID
CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH
20:5 n-3
DOCOSOHEXAENOIC ACID - YOU CAN DO THIS ONE!
Fatty acid oxidation
Degradation of fatty acid through oxidation of C = -oxidation
Mitochondria
FA need to cross 2 membranes to reach matrix
Not as CoAs but as acyl-carnitine
CPT-I, cytosol; CPT-II, matrix
Separate pools of mitoch/cytosol.
CoAs
ATPs
NAD+
Side Notes on Fatty Acid +
Lipoprotein Metabolism
NORMAL TRIGLYCERIDE METABOLISM
Key concepts: absorption
Triglyceride (i.e. energy) assimilation is key to the survival of
the organism.
Dietary triglyceride must be hydrolyzed to fatty acids,
mono-glycerides and glycerol prior to absorption.
Fatty acids must partition to micellar phase for absorption.
For transport, triglyceride must be reconstituted from
glycerol and fatty acid and incorporated into
chylomicrons.
Structures of Fatty Acids
O
C 18:0
HO
O
C cis-18:1 -6
HO
O trans-18:1 -6
C
HO
O
C 18:2 -6
HO
O
C 18:3 -3
HO
Structures of Fatty Acids
O
C 16:0 (palmitic)
HO
O
C cis-18:1 -6 (oleic)
HO
O trans-18:1 -6 (elaidic)
C
HO
O
C 18:2 -6 (linoleic)
HO
O (alpha
C 18:3 -3 linolenic)
HO
O
C 20:5 -3 (EPA)
HO
Fatty Acid and Triglyceride Flux
FATTY
ACIDS
(ALBUMIN)
TG (VLDL)
LIPO-
PROTEIN
LIPASE
TG (CHYLO-
MICRONS)
Dietary Carbohydrate Increases
VLDL Production
Plasma
Dietary Triglyceride
Carbohydrate (VLDL)
Lipoprotein
Metabolism
Cholesterol Ester Synthesis
Acyl-Cholesterol Acyl Transferase (ACAT)
Cholesterol
COOH HO Cholesterol
Ester
COO
Lecithin-Cholesterol Acyl Transferase (LCAT)
Lysolecithin
COO COO
COO COO
+ N OPOO + N OPOO
Pancreatic Lipase Movement
Most pancreatic
lipase is secreted
into the pancreatic
duct, but some moves
back into capillaries.
Chylomicron Role in Pancreatitis
Pancreatic lipase acts
on chylomicrons
adherent to capillary
endothelium, producing
fatty acid anions, or
soaps. By detergent
action, cell membranes
are disrupted, releasing
more lipase, and
additional fatty acid
anions are produced in
a vicious cycle.
Apolipoproteins
apoA-I HDL structural protein; LCAT activator;RCT
apoA-II HL activation
apoA-IV Tg metabolism; LCAT activator; diet response
apoB-100 Structural protein of all LP except HDL
apoB-48 Binding to LDL receptor
apoC-I Inhibit Lp binding to LDL R; LCAT activator
apoC-II LpL activator
apoC-III LpL inhibitor; antagonizes apoE
apoE B/E receptor ligand *E2:IDL; *E4: Diet Responsivity
Metabolic Relationships
Among Lipoproteins
1.
VLDL LDL
2. 3. TG
HDL
Lipoprotein
Lipase`
TRIGLYCERIDES
SMALL
HDL DENSE LDL
Role of CETP in Triglyceride/
Cholesteryl Ester Exchange
TG TG
VLDL CETP HDL HDL CETP LDL
CE CE
Role of Triglycerides in Producing
Small Dense LDL or HDL
CETP Lipase
CE CE CE
TG
TG TG
1. CE exchanged for TG 2. TG removed
Dyslipidemia of Metabolic
Syndrome
UNINHIBITED
LYPOLYSIS
FREE
FATTY
ACIDS
TG TG
VLDL CETP HDL CETP LIPASE
LDL sdLDL
CE CE
FATTY ACIDS
GLYCEROL
HDL
CATABOLISM
Peroxisome Proliferator-Activated Receptor:
A Nuclear Receptor for Metabolic Genes
a, Basic mechanism of action of
nuclear hormone receptors: bind
to a specific sequence in the
promoter of target genes (called
hormone response elements), and
activate transcription upon
binding of ligand. Several nuclear
hormone receptors, including
the retinoic acid receptor, the
vitamin D receptor and PPAR, can
bind to DNA only as a heterodimer
with the retinoid X receptor, RXR,
as shown. b, some PPAR and
PPAR ligands.
Kersten et al. Roles of PPARs in health
and disease. Nature 2000; 405: 421-424
LDL
and HDL metabolism
PPAR PPAR
Tissues: Liver, kidney, heart, Tissues: Adipose tissue and
muscle. intestine.
Ligands: fatty acids, fibrates Ligands: arachidonic acid,
Glitazones
Actions: Stimulate production Actions: increase expression of
of apo A I, lipoprotein lipase, ABC A-1, increase FFA synthesis
increase expression of ABC and uptake by adipocytes, increase
A-1, increase FFA uptake and insulin sensitivity (?)
catabolism, decrease FFA
and VLDL synthesis.
* Peroxisome Proliferator Activated Receptor
HDL and Reverse Cholesterol Transport
HDL and Reverse Cholesterol Transport
Tangier Disease
HDL and Reverse Cholesterol Transport
HDL and Reverse Cholesterol Transport
HDL and Reverse Cholesterol Transport
HDL and Reverse Cholesterol Transport
LDL-R
HDL and Reverse Cholesterol Transport
LDL-R
50% of HDL C may
Return to the liver
On LDL via CETP
Lipoprotein(a), or Lp(a)
Apo(a)
An atherogenic lipoprotein
containing apo(a) and apoB.
LDL
20-30% of people have levels -S-S-
suggesting C-V risk.
Black subjects have Lp(a)
normal range twice as high
as white and Asiatic subjects.
Apo(a) sequence similar to plasminogen, and Lp(a)
interferes with spontaneous thrombolysis.
Lp(a) levels highly genetic, resistant to diet and drug
therapy, although niacin may help.
