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
Tissues: Liver, kidney, heart,
muscle.
Ligands: fatty acids, fibrates
Actions: Stimulate production
of apo A I, lipoprotein lipase,
increase expression of ABC
A-1, increase FFA uptake and
catabolism, decrease FFA
and VLDL synthesis.
* Peroxisome Proliferator Activated Receptor
PPAR
Tissues: Adipose tissue and
intestine.
Ligands: arachidonic acid,
Glitazones
Actions: increase expression of
ABC A-1, increase FFA synthesis
and uptake by adipocytes, increase
insulin sensitivity (?)
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.