METABOLISM OF LIPIDS

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METABOLISM OF LIPIDS
PA BIOCHEMISTRY (Lec. 34) BAHS 501, FALL 2003
Jack Kinkade, Ph.D., M.P.H. 4135 Rollins Research
Center jkinkad_at_emory.edu 404-727-5965
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OBJECTIVES

• To learn the major classes of lipids found in the
  diet.
• To appreciate the structural and functional
  diversity of lipids.
• To learn how the physical properties of lipids
  influence the manner in which the body must
  handle them.
• To understand how dietary lipids are broken down,
  absorbed by mucosal cells of the intestine,
  resynthesized and transported to tissues.

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LIPIDS

• Biochemicals that are extracted by organic
  solvents
• The most structurally diverse class of compounds
  in nature
• Found in Cell membranes Lipoproteins Permeabi
  lity layer of skin Fat storage depots
  (adipocytes) Secreted waxes Oils Etc.

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Biological Functions of Lipids

• Energy storage
• Cellular membrane components Structural and
  Bioactive
• Precursors of hormones, vitamins, regulators

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Classes of Lipids
phospho lipids
fatty acids
glycolipids
steroids
sphingolipids
triacylglycerol
vitamins A,D,E,K
cholesterol
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TRIACYLGLYCEROLS

• Triacylglycerols (also called triglycerides) are
  efficient storage forms for energy because they
  combine three fatty acids (such as the one shown
  below), which can be oxidized to a large number
  of ATPs
• plus a glycerol group, which can be converted to
  (and formed from) glucose

OR
OH
HO
Glucose
RO
OR
OH
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Structures of the major classes of membrane
lipids Fatty acids An example of an unsaturated
fatty acid is
Oleic acid (C181 ?9)

• The fatty acid nomenclature depicts the total
  carbon number (i.e., a C18 fatty acid has an
  alkyl chain of 18 carbons) followed by the number
  of double bonds, and the position of the double
  bonds, numbering from the carboxyl end ( the ?
  nomenclaure) or from the methyl end (the n or ?
  nomenclature).
• Focus particularly on the following
• Palmitic acid C160
• Stearic acid C180
• Oleic acid C181?9 C181?9
• Linoleic acid C182?9,12 C182?6,9
• Linolenic acid C183?9,12,15 C183?3,6,9
• Arachidonic acid C204?5,8,11,14 C204?6,9,12,15

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Biological Membranes
Liver Plasma Membrane
46 PC 15 SM 22 PE 9 PS 6
PI others Cholesterol 0.5 to 1.1 ratio of
phospholipids
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Major Membrane LipidsGlycerophospholipids

• Glycerophospholipids
• Most abundant lipids of membranes
• Composition varies with tissue and cellular
  membrane
• Variability in fatty acyl (R) groups for
  phospholipids

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Major Membrane LipidsSphingolipids

• High levels in myelin and nerve tissue but
• found in most other tissues
• Glycosphingolipids typically found on
• extracellular leaflet of plasma membrane
• (function in cellular recognition, receptors,
• etc.)
• Variability in R-group chain length
• and saturation

HO-CH-CHCH-(CH2)12-CH3
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Cholesterol and Derived Lipids

• Cholesterol
• Lipoproteins

Cholesterol Esters Steroids Bile Acids Vitamin D
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Triacylglycerols and other lipids are HYDROPHOBIC
Alkyl chains do not form dipolar or hydrogen
bonds with water, and instead try to avoid water
(this is called hydrophobic). In doing so,
triacylglycerols (and most other lipids) will
aggregate to reduce the area of the surface that
is in contact with water.
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Why do some lipids form bilayers rather than
droplets?
They are composed of both hydrophilic and
hydrophobic moieties, hence are termed
amphiphilic or amphipathic (depending on whether
you are an optimist or a pessimist).
Polar hydrophilic
Non-polar hydrophobic
Aggregation of amphiphilic compound to minimize
contact between hydrophobic surface and water
3D Sphere (liposome)
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A monolayer of amphiphilic lipid(s) can stabilize
droplets of hydrophobic lipids (e.g.,
triacylglycerols) against aggregation
TG
Collision without aggregation
TG
TG
TG
This is the principle behind stabilization of
triacylglycerols in circulation by formation of
lipoproteins comprised of TG, cholesterol,
phospholipids and proteins
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Overview
Lipids constitute at least one-third of the
calories consumed by most Americans (60-150 g per
day). Although they are consumed in
over-abundance by much of the industrialized
world today, it was advantageous to utilize these
compounds efficiently throughout human evolution
therefore, lipid digestion, absorption, and
transport is a highly complex and efficient
process. There is a small amount of lipid
digestion in the mouth and stomach (catalyzed by
lingual lipase), but most takes place in the
upper intestine.
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Stomach
Dietary fat
Gastric motility
-
Cholecystakinin (CCK)

Dietary fat
Pancreas
Digestive enzymes bicarbonate Bile
Secretin
Liver
Bile
Gall bladder
Upper intestine
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• Hydrolysis of triacylglycerols (quantitatively
  the most significant class of lipid in the diet),
  involves the action of pancreatic lipase (plus
  co-lipase) -- a 1,3 lipase so that the major
  products are 2-monoacylglycerol plus two mol of
  fatty acid some (estimated to be as much as half
  of the monoacylglycerol) is cleaved to glycerol
  plus fatty acid by humans.

Removal of fatty acids at positions 1 and 3
(100 complete)
Fatty acid _at_ 2 ( 50)
O
R1
OH
O
OH
O
O
O
O
H
H
H
HO
OH
OH
R2
OH
R2
2-Monoacylglycerol
Glycerol
Triacylglycerol
Diacylglycerol
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Changes in physical state during triacylglycerol
digestion. TG triacylglycerol, DG
diacylglycerol, MG monoacylglycerol, FA fatty
acid
For lipid digestion, the droplets must be broken
into smaller particles by formation of micelles
with bile acids
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Bile Acids are Detergents that Emulsify the Lipids
Intestinal mixed micelle
Emulsification (dispersion of the lipid phase
into smaller droplets) increases the lipid-water
interface at which the various hydrolytic enzymes
are active as well as solubilizing the lipids.
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The Different Classes of Lipids are Degraded by a
Variety of Pancreatic and Intestinal Lipases
pancreatic lipase co-lipase
phospholipase A2
These lipid products form mixed micelles with the
bile acids and are absorbed through the brush
border membrane of the intestinal mucosal cells.
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LIPID TRANSPORT/SECRETION
Lipid transport involves not so much the
movement of the initial digestion
products,e.g. fatty acids, but rather the
RESYNTHESIS of complex lipids (such as
triacylglycerols, phospholipids, etc.) which are
packaged into chylomicrons along with
cholesterol, fat soluble vitamins, and
essentially all of the other hydrophobic
compounds (including drugs, pesticides, and other
xenobiotics) that have been taken up.
Chylomicrons are lipoproteins that contain a
structural protein named apoB-48.
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Generalized Structure of Plasma Lipoproteins
Spherical particle model consisting of a core of
triacylglycerols (yellow Es) and cholesterol
esters (orange drops) with a shell 20 Å thick
of apolipoproteins (lettered), phospholipids, and
unesterified cholesterol. Apolipoproteins are
embedded with their hydrophobic edges oriented
toward the core and their hydrophilic edges
toward the outside.
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Chylomicrons ( )
deliver triacylglycerols to the tissues for
energy utilization. Chylomicron remnants (
) are returned to the liver
Chylomicron Remnants
Chylomicrons
Lipoprotein Lipase
Free FAs Glycerol
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Chemical Composition of the Different Plasma
Lipoprotein Classes
Percent Composition of Lipid Fraction
Total Protein ()
Total Lipid ()
Lipoprotein Class
Esterified Cholesterol
Unesterified Cholesterol
Phospholipids
Triacylglycerols
HDL2? HDL3? LDL IDL VLDL Chylomicrons
40-45 50-55 20-25 15-20 5-10 1.5-2.5
55 50 75-80 80-85 90-95 97-99
35 20-25 15-20 22 15-20 7-9
12 12 35-40 22 10-15 3-5
4 3-4 7-10 8 5-10 1-3
5 3 7-10 30 50-65 84-89