A.K.P.

C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS JEREMIAH 29:11

LIPOPROTEIN METABOLISM AND DISORDERS LIPOPROTEIN PATHWAY

LIPOPROTEIN METABOLISM o Cholesterol and Triglycerides are insoluble in blood

o Lipoproteins responsible for transporting
 All the lipids contained in plasma, including fat, triglycerides and cholesterol throughout the body
phospholipids, cholesterol, cholesterol ester and
fatty acid, exist and transport in form of
lipoprotein.

 STRUCTURE:
o Non-covalent assemblies of lipids and proteins
o LP Core
o Triglycerides
o Cholesterol esters

o LP Surface o CLASSIFICATION OF LIPOPROTEINS, BASED ON:

o Phospholipids  Size
o Proteins  Composition
o Cholesterol  Present apolipoproteins

o PRO-ATHEROGENIC
o Contribute towards fatty deposits in arteries
resulting in atherosclerosis

o ANTI-ATHEROGENIC
o Elevated HDL levels reduces risk of
atherosclerosis
 Function as transport vehicles for triacylglycerol and
cholesterol in blood. LIPOPROTEIN PATHWAY:

Dietary lipids incorporated into chylomicrons in the

intestines
Exogenous lipoprotein pathway
Source of lipids is from outside the body

Enzyme lipoprotein lipase (in muscle and adipose

tissue) breaks down triglycerides in chylomicrons to
release fatty acids.
A.K.P.C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS JEREMIAH 29:11
LIPOPROTEIN NOMENCLATURE – COMPOSITION AND FUNCTIONS OF APO-LIPOPROTEINS
SEPARATION
1. To combine and transport lipids
CM  VLDL  LDL  HDL 2. To recognize the lipoprotein receptors
o Apo-B100 is the ligand for LDL receptors
CM VLDL LDL HDL o Apo-A1 is the ligand for HDL receptor
MAJOR apoB 48 apoB 100 apoB 100 apoA-I
PROTEIN
3. Activators for certain enzymes involved in
MAJOR TG TG CE CE
LIPID lipoprotein metabolism
o Apo C II activates lipoprotein lipase
1. ELECTROPHORESIS METHOD (Low to High) o Apo-A1 activates LCAT (Lecithin Cholesterol
o CM (Chylomicron) Acyltransferase, formation of cholesterol esters
o B-lipoprotein in lipoproteins)
o Pre B-lipoprotein
o Alpha-lipoprotein APOLIPOPROTEINS
APOLIPOPROTEIN MOLECULAR LIPOPROTEIN FUNCTION
WEIGHT ASSOCIATION (IF KNOWN)
2. ULTRA CENTRIFUGATION METHOD (Fast to Slow) ApoA-I 28,331 HDL Activates
o CM (Chylomicron) LCAT:
o Very low density lipoprotein (VLDL) interacts
with ABC
o Low density lipoprotein (LDL)
transporter
o High density lipoprotein (HDL) ApoA-II 17,380 HDL
ApoA-IV 44,000 Chylomicrons,
HDL
ApoB-48 240,000 Chylomicrons
ApoB-100 513,000 VLDL, LDL Binds to LDL
receptor
ApoC-I 7,000 VLDL, HDL
ApoC-II 8,837 Chylomicrons, Inhibits
VLDL, HDL lipase
ApoD 32,500 HDL
ApoE 34,145 Chylomicrons, Triggers
VLDL, HDL clearance of
LIPIDS ARE TRANSPORTED AS LIPOPROTEINS VLDL and
Chylomicron
remnants
 All lipids in plasma are transported in the form of
lipoproteins. METABOLISM OF CHYLOMICRON
 Transport dietary lipids from intestine to liver
(exogenous)  CHYLOMICRONS
 FUNCTION: Transport exogenous TG (dietary fat)
from the intestine to the peripheral tissues; where
 Transport lipids from liver to peripheral tissues
TG is used as an energy source or stored in adipose
(endogenous)  VLDL (VERY LOW DENSITY
tissue
LIPOPROTEINS)
STEP 1:
APOLIPOPROTEINS (APOPROTEINS) o NASCENT CHYLOMICRONS are formed in the
intestinal mucosa and pass to the blood stream
 They are the protein components of lipoproteins
 CONSISTING: o Nascent chylomicrons consist of:
o 60% of some lipoproteins (HDL)  Rich in dietary TG + minimal amount of dietary
o 1% of some lipoproteins (chylomicrons) cholesterol + Apo B, which is necessary for
- Largest and least dense assembly of the chylomicron
o The MAJOR APOPROTEIN of HDL is designated  The lipid component is very high, thus, it is of
A, and of LDL is Apo-B which is also found in least density.
VLDL and chylomicorn.
A.K.P.C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS
STEP 2:
o After passage to blood, addition to ApoC and APoE
from HDL leads to the formation of mature
chylomicron.
STEP 3:
o Capillary lipoprotein lipase (LPL), activated by Apo
C, hydrolyzes TG present in chylomicrons into 
fatty acids + glycerol + producing chylomicron
remnant (chylomicron containing less TG and more
cholesterol + Apo E +Apo B)  which are taken up
by the liver through endocytosis.
STEP 4:
1. GLYCEROL  is phosphorylated in the liver by
glycerol kinase  glycerol 3-phosphate which is
used to synthesize more VLDL.
2. FREE FATTY ACIDS  enter the adipose tissue in to
produce TG for storage.
In muscle  the fatty acids are oxidized to provide
energy.
3. Apo C returns HDL
4. CHYLOMICRON REMNANTS  attach to Apo E
receptors in the liver and are endocytosed
5. Dietary cholesterol delivered to the liver via
chylomicron remnants is used for  bile acid
synthesis.
6. Excess cholesterol is  excreted in bile.
METABOLISM OF VLDL AND PRODUCTION OF LDL
A. 1-SYNTHESIS OF NASCENT VLDL
 Nascent VLDL is synthesized in the liver.
 They transport TG synthesized in the liver
(endogenous fats) to peripheral tissues to be
available as energy source or for storage.
 Alaso contain some cholesterol (17%)
 Its apoprotein is ApoB-100
B. 2-CONVERSION TO MATURE VLDL
 Nascent VLDL are released into the blood by the
liver
 They receive Apo-C11, E and cholesterol esters
from HDL in plasma, converting to mature VLDL
JEREMIAH 29:11
C. DEGRADATION BY PLASMA LIPOPROTEIN LIPASE
(LPL)
 In peripheral tissues, adipose tissue and
muscles, VLDL/TG are hydrolyzed by lipoprotein
lipase (LPL).
 The LPL (activated by Apo C of VLDL) hydrolyses
TG/VLDL into fatty acids + glycerol +VLDL
remnants (intermediate-density lipoproteins:
IDL); containing less of TG and more cholesterol
 A small part of VLDL remnant is take up by the
liver, by receptor-mediated endocytosis
 The major fraction of VLDL remnant further
loses TG, so as to be converted to LDL.
 This conversion of VLDL to IDL and then to LDL
is referred to as: lipoprotein cascade pathway.
LOW DENSITY LIPOPROTEINS (LDL)
 All LDL arise normally from VLDL metabolism
 Bad cholesterol
 Structure of LDL:
o Apo-B100 is the ONLY apolipoprotein in LDL
particles
o LDL is a cholesterol rich particle, because it has
minimum TG
THE FUNTION OF LDL:
1. Transport cholesterol from liver to peripheral
tissues
2. Regulate cholesterol synthesis
3. LDL is important source of cholesterol to extra
hepatic tissues
4. It is the major transport form of cholesterol / blood
5. The liver has a major role in controlling LDL
cholesterol / plasma due to:
a. Most of LDL receptors are present in the liver
b. The liver synthesized cholesterol
c. It removes cholesterol from lipoprotein
remnants
d. It is the only organ that can excrete cholesterol
through bile
A.K.P.C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS JEREMIAH 29:11
RIRSK FACTOR CLINICAL SIGNIFICANCE OF LIPOPROTEINS

 High levels of LDL-cholesterol increase the risk of  FATTY LIVER

atherosclerosis.  Is an abnormal accumulation of certain fats
(triglycerides) inside liver cells
FATES OF FREE CHOLESTEROL TRASNPORTED TO THE  Hepatic triacylglycerol synthesis provides the
CELLS BY LDL: immediate stimulus for the formation and
secretion of VLDL
1. Incorporated into cell membranes  Impaired VLDL formation or secretion leads to
2. Metabolized to steroid hormones non-mobilization of lipid components from the
3. Re-esterified and stored liver, results in fatty liver
4. Excreted through liver
 FATTY LIVERS FALL INTO TWO MAIN
METABOLISM OF HIGH DENSITY LIPOPROTEINS (HDL) CATEGORIES:

 They are formed by the liver cells and intestinal a. MORE SYNTHESIS OF TRIGLYCERIDES
mucosa o High carbohydrate diet
 These are the smallest and most dense lipoprotein o High fat feeding
particles o Starvation
 They contain large amount of proteins (50-60%) and o Diabetes mellitus
very little triglycerides, while the predominant lipid
is phospholipid. High carbohydrate diet stimulates de novo fatty acid
 Good cholesterol synthesis by providing excess of Acetyl CoA ad high
fat feeding provides more flux of fatty acids from the
diet that can be esterified to provide excess
FUNCTION OF HDL
triglycerides.

1. Removing free cholesterol from extra hepatic b. DEFECTIVE VLDL SYNTHESIS

tissues  and esterifying it using plasma enzyme o The second type of fatty liver is usually
called lecithin-cholesterol-acyl transferase (LCAT). due to a metabolic block in the
The Apo A1 of HDL activates LCAT production of plasma lipoproteins, thus
following triacylglycerol to accumulate.
They transport cholesterol esters  to the liver
THE LESION MAY BE DUE TO:
HEPATIC LIPASE (similar to LPL) hydrolyses HDL and
cholesterol esters  free cholesterol, which either: 1. A BLOCK IN APOLIPOPROTEIN
o Enters in the formation of lipoprotein SYNTHESIS:
o Converted to bile acid
o Excreted into bile for removal from the body  Protein energy malnutrition
 Impaired absorption
 HDL is very safe  Presence of inhibitors of
 The level of HDL in serum s inversely related to endogenous protein synthesis
atherosclerosis and myocardial infarction. (carbon tetra chloride, puromycin,
 HDL is also known as good cholesterol ethionine, heavy metals)
 Hypobetalipoproteinemia –
2. A major function of HDL is to act as a source for defective Apo B gene can cause
Apo C and Apo E that are required in the impaired synthesis of Apo B protein
metabolism of chylomicrons and VLDL
2. A FAILURE IN PROVISION OF
3. Transport phospholipids from liver to tissues PHOSPHOLIPIDS THAT ARE FOUND IN
LIPOPROTEINS
A.K.P.C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS JEREMIAH 29:11
 A deficiency of choline, a lipotropic thus prevent the formation of fatty liver called
factor can cause impaired lipotropic agents.
formation of phosphatidyl choline
(Lecithin), a glycophospholipid PRIMARY DISORDERS OF PLASMA LIPOPROTEINS
 Methionine deficiency can also (DYSLIPOPROTEINEMIAS)
cause impaired choline synthesis
 Inositol deficiency  Inherited defects in lipoprotein metabolism lead to
 Deficiency of essential fatty acids the primary condition of either hypo- or
can also cause impaired PL hyperlipoproteinemia.
synthesis.  In addition, diseases such as:
o Diabetes mellitus
3. IMPAIRED GLYCOSYLATION o Hypothyroidism
 Orotic acid also causes fatty liver o Nephrotic syndrome
 It interferes with glycosylation of o Atherosclerosis is associated with secondary
the lipoprotein, thus inhibiting abnormal lipoprotein patterns that are very
release, and may also impair the similar to one another of the primary inherited
recruitment of triacylglycerol to the conditions.
particles  All of the primary conditions are due to a defect at a
 In conditions of orotic aciduria stage in lipoprotein formation, transport, or
(disorder of pyrimidine nucleotide degradation.
biosynthesis), fatty liver can be
observed DYSLIPOPROTEINEMIAS
NAME DEFECT CHARACTERISTICS
4. IMPAIRED SECRETION OF VLDL HYPOLIPOPROTEINEMIAS
 Oxidative stress is a common cause Abetalipoproteinemi NO chylomicrons, Rare; blood
a VLDL or LDL are acyglycerols
of membrane disruption of
formed because of Low; intestine and
lipoproteins defect in the liver accumulate
loading of Apo B acylglycerols.
 ALCOHOLIC FATTY LIVER with lipid
 Alcoholism leads to fat accumulation in the Intestinal
malabsorption
liver, hyperlipidemia, and ultimately cirrhosis. Familial alpha- all have low or Hypertriacylglycerole
 The fatty liver is caused by a combination of lipoprotein near absence of mia due to absence
impaired fatty acid oxidation and increased deficiency HDL of Apo C-II
lipogenesis, which is thought to be due to Low LDL levels
Tanger disease
changes in the [NADH]/[NAD] redox potential in Atherosclerosis in
the liver Fish eye disease the elderly.
 Also to interference with the action of
transcription factors regulation the expression Apo-A-1 deficiencies
of the enzymes involved in the pathways HYPERLIPOPROTEINEMIA
Familial lipoprotein Hypertriaglycerole Slow clearance of
lipase deficiency mia due to chylomicrons and
FATTY LIVER AND LIPOTROPIC AGENTS (TYPE 1) deficiency of LPL VLDL
Low levels LDL and
Abnormal LPL or HDL
LIPOTROPIC AGENTS, SUCH AS: Apo-C II deficiency No increased risk of
causing inactive coronary disease
 Choline LPL.
 Inositol Familial Defective LDL Elevated LDL levels
 Methionine and other essential amino acids hypercholesterolemi receptors or and
a (TYPE II a) mutation in ligand hypercholesterolemi
 Essential fatty acids region of Apo – a, resulting in
 Antioxidant vitamins B100 atherosclerosis and
 Vitamin B12, Folic Acid coronary heart
 Synthetic antioxidants which have the apparent disease
Familial TYPE III Deficiency in Increase in
effect of removal of fats from the liver cells, and
A.K.P.C – PRELIM – WEEK 2 (CC1): LIPOPROTEIN METABOLISM AND DISORDERS JEREMIAH 29:11
hyperlipoproteinemi remnant clearance chylomicron and
a (broad beta by the liver is due VLDL remants
disease, remnant to abnormality in
removal disease, Apo-E Causes
familial hypercholesterolemi
dysbetalipoproteine a, xanthomas, and
mia) atherosclerosis
Familial Overproduction of High cholesterol,
hypertriaclyglycerole VLDL often VLDL
mia (TYPE IV) associated with Subnormal LDL and
glucose HDL
intolerance and Associated with
hyperinsulinemia diabetes mellitus and
obesity
Hepatic lipase Deficiency of the Patients have
deficiency enzyme leads to xanthomas and
accumulation of coronary heart
large disease.
triacylglycerol-rick
HDL and VLDL
remnants