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1) OBESITY & high plasma triglycerides
Adipose cells, adipocytokines
.
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White fat cells store large lipid droplets of triglycerides and cholesterol ester.
Leptin (167aa) synthesised and secreted, peptide hormone, binds to receptors
in hypothalamic nuclei “satiety center.”
Regulates energy.Signals a decrease in appetite. Prooxidant.
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Adiponectin (244aa) , most abundant protein in adipocyte, (similar structure
to TNFα) & released into the blood. Higher in females. Antioxidant.
 adipocyte oxidative stress (insulin activates NADPH oxidase (Nox4)
body weight , mitoch.fatty acid oxidation, gluconeogenesis, insulin
resistance. Insulin causes lipogenesis and fatty acid release ( fatty liver) .
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Plasma adiponectin decr. & leptin incr. in obesity (promotes breast cancer).
Brown fat (babies) mitochondria make heat.
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Adipocyte dysfunction & Metabolic disease
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Obesity due to overnutrition (high fat or sugar diet ) & inactivity
causes metabolic disease .
• Insulin resistance & diabetes mellitus
• Hypertension
• Hyperlipidemia , nonalcoholic steatohepatitis (NASH),
alcoholic liver disease, chronic hepatitis, liver cancer
• Therapy:
caloriesexercise,taurine,salicylate,thiazolidinediones,
• Research : how to increase adiponectin levels
• J.Gastroenterol(2008)43,811-822,Clinical Chemistry (2008)54,945-55
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Fatness increases cancer risk
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Fatness cancer rate may exceed cancer from smoking soon.
Breast cancer, esophagus, colorectal, pancreas, ovary.
gall bladder,endometrium, liver (after cirrhosis) NASH.
NOT prostate,bladder, mouth, lung, skin, cervix,
nasopharynx,skin cancer.
• Associated with energy-dense foods,fast food,sugary
drinks,sedentary living,TV/computers.
• 2007 WCRF/AICR report
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Figure 1 Following chronic alcohol ingestion, endotoxin is released from certain intestinal bacteria.
Endotoxin moves from the gut into the bloodstream and the liver where it activates Kupffer cells- a type of
immune cell (resident liver macrophages) - by interacting with CD14 causing nuclear factor kappa B (NFκB)
production.This generates superoxide radicals (O2) and various signaling molecules (the cytokine TNF–α)
which injures hepatocytes. (Alcohol Res Health. 2003; 27(4):300-6.)
2) High plasma cholesterol and
atherosclerosis
A.
B.
C.
D.
E.
F.
G.
H.
Clinical chemistry
Fat Absorption
Liver cell synthesis of LDL and HDL
Cholesterol Synthesis
Drug Therapy
Fibroblasts and other extrahepatic tissues for
membrane biosynthesis
Incr. heart attacks,strokes,atheroscelerosis
Genetic Disorders
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Lipoproteins, Cholesterol and Atherosclerosis
A) Clinical chemistry - Lipoproteins
• Conjugated proteins in which the prosthetic group are lipids:
• Lipoproteins responsible for the transport/distribution of lipids:
- Lipid hormones
- Lipids absorbed by the intestine
- Fat-soluble vitamins
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Plasma cholesterol >6.2mM (change diet); 5.5-6.2mM (borderline); <5.5mM normal
Percent contribution of saturated fat and cholesterol from fats/oils,
meats, dairy products and eggs in the US diet.
Biochim. et Biophys. Acta 1529 (2000) 310-320
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A lipoprotein:
Horton Fig 17-5
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B) Stage 1 - Fat Absorption
Chylomicrons
•Found in lymph draining the intestine not hepatic
portal systems
• Largest ones are microscopically visible (diameter
500 nm) (floats upon centrifugation)
• Responsible for the lipemic (milky turbidity) of the
blood following food digestion and disappears at 5 hours
Contains 1% protein - formed by intestinal cell
• Triglycerides (apo AI and II, B)
Chylomicron
VLDL
LDL BAD
HDL GOOD
Particle Size Electroph.
(nm)
>75
25-75
A2
19-26
B
7-19
A1
Origin
Intestine
Liver
VLDL
Liver, intestine
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Dietary cholesterol  chylomicron & HDL formed in intestinal epithelial cell
 remnant  lymph vessel taken up by adipose cells & extrahepatic tissues
B48 M.W. = 300,000
(chylomicrons,
chylomicron remnants)
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C) Stage 2 : LDL activity and function
LDL(apoB100) synthesised by liver moves cholesterol to the tissues
(taken up by the apoB100 receptor of tissues).
LDL carries 75% plasma cholesterol and HDL carries 25%.
1. Intestine
2. Liver
(Synthesis)
chylomicrons
VLDL
tissues for oxidation
adipose tissue
for storage
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Liver cell synthesis of LDL,VLDL and HDL
B-100
A,C,E
i.e. LDL, VLDL, HDL
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Electron micrograph of a
part of a liver cell actively
engaged in the synthesis
and secretion of very low
density lipoprotein
(VLDL). The arrow points
to a vesicle that is releasing
its content of VLDL
particles.
Liver mitochondrial fatty acid oxidation inhibited by some drugs causing
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FATTY LIVER
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F) Stage 3- Fibroblasts and other extrahepatic tissues - cholesterol taken up
for membrane biosynthesis
Extrahepatic tissues obtain cholesterol from plasma LDL & NOT by synthesis
STEPS:
a) ApoB100 protein of LDL binds to receptor in coated
pits
b) Receptor-LDL complex is internalised by endocytosis
c) Vesicles containing LDL fuse with lysosomes (proteases, esterases)
LDL Protein
proteases
LDL Cholesterol esters
amino acids
esterases
cholesterol + fatty acid
LINOLEATE
LDL receptor returns to plasma membrane
(10min. - turnover ever 24 hours)
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Steps (cont’d)
d) Free cholesterol in the cell is used or stored
Cholesterol
+ Linoleate
Acyl-CoA: cholesterol
acyl transferase
Membrane biosynthesis
Cholesterol ester
i.e., store for cholesterol
Regulation:
When excess, the synthesis of new LDL
receptors is stopped, therefore LDL not
taken up by cells
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The LDL receptor
The LDL receptor consists
of five domains with
different functions: an
LDL-binding domain, 292
residues; a domain bearing
N-linked sugars, 350
residues; a domain bearing
O-linked sugars, 58
residues; a membranespanning domain, 22
residues; and a cytosolic
domain, 50 residues.
Membrane
spanning
domain
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Four Mutations affecting LDL receptors
1) no receptor is synthesised
2) receptors are synthesised but lack signals for transport
 don’t reach plasma membrane
3) receptors reach cell surface but don’t bind LDL
normally
4) receptors don’t cluster in coated pits
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Genetic disorders (cont.)
e.g. Familial hypercholesterolemia (Type II)
- Autosomal dominant trait 1:500
- Cholesterol 680 mg/100 mL instead of 175 mg/100 mL
- Die of heart disease before 20 years (homozygous)
- Die of heart disease before 40 years (heterozygous– inherit one defective
and one normal gene)
1.LDL receptor is unable to bind to coated pitsrandomly distributed
in membrane LDL binds but can’t be absorbed by endocytosis
2. Faulty LDL receptor formed which can’t bind LDL
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Extrahepatic tissue(e.g.fibroblasts) take up cholesterol via LDL receptors
and store it as cholesterol esters in lysosomes
Voet et al., Fig 19-37
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Cholesterol Ester Synthesis
Endoplasmic reticulum
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LYSOSOMES recycle proteins,lipids,nucleic acids
Autophagic vacuole
Aged proteins,
Nucleic acids,
lipids
FAD
Amino acids
Cholesterol
Nucleotides
Fatty acids
Acid proteases (cathepsins)
Cholesterol ester esterase
Nucleases
Acid phospholipases
Require acid pH
ROS
H+
NADH
Cyt b5
CoQ
ACID pH
Stores dietary CoQ
CoQ reduction maintains acid pH
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Arch Biochem Biophys. 375, 347-54, (2000).
G) Atherosclerosis – cholesterol plaque formation
An atherosclerotic plaque
(marked by the arrow)
blocks most of the lumen of
this blood cell. The plaque
is rich in cholesterol.
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Atherosclerosis mechanism: oxidised LDL taken up by macrophage
scavenger receptors
LEUKOCYTES, ENDOTHELIAL CELLS
NH 2
Liver
(H2O2/Fe or Cu)
NH 2
B100
B100
OOH
LDL
LIPID PEROXIDE
ANTIOXIDANT
e.g. PROBUCOL
(500mg/day)
HC
-SCISSION
C CHO
H
MODIFIED
NH SCHIFF
BASE
LDL
B100
M.W.
ELECTROPH. MOBILITY
FLUORESC.
NH 2
O
B100
+
O
H
H
MALONDIALDEHYDE
Don't bind to apo B LDL receptor
or peripheral cells
BUT recognised by scavenger
receptor of macrophage
macrophage
accumulates chol.
transformation
Forms atherosclerotic plaque
Foam Cell
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