7 Overview of Lipid

Overview of Lipid, Apolipoprotein and
Lipoprotein
Lipid Metabolism and the 2015
compounds:
Updated CPG
Relatively in insoluble
water the Management of
Dyslipidemia in the Philippineslasma
Therefore, (aqueous) as Lipoprot in eins
they are transported
Lourdes Ella G. Santos, MD
1. VLDL particles
a. contain apo B48 as their main

lipoprotein.
b. acquire apo C’s and apo E.
c. exchange cholesteryl esters for
triglycerides from HDL.
d. are larger than chylomicrons.
2. Reverse cholesterol transport pathway
a. occurs in the intestinal pathway.

b. constitutes transfer of phospholipids onto
nascent HDL particles mediated by
lipoprotein lipase (LPL).
c. facilitates transfer of cholesterol from HDL
to VLDL remnants so that it can be
metabolized in the liver.
d. involves a unidirectional transfer of
constituents between lipoproteins.
3. True of LDL particles
a. Each LDL particle contain several molecule

of apo B.
b. LDL-R is localized in a region of the plasma
membrane rich in the protein cathepsin.
c. Normally triglycerides constitute only 4%
to 8% of the LDL mass.
d. A relative increase in cholesteryl esters
leads to smaller, denser LDL particles.
4. High density lipoprotein
a. contains apo A-I, the main protein of

HDL, synthesized by the intestine and liver.
b. precursors, called nascent HDL, are
easily measured in the fasting lipid profile.
c. provides cholesterol to steroid
hormone– producing tissues and the liver
through the scavenger receptor SR-B1.
d. All of the above are true.
5. In type II hyperlipidemia
a. affected subjects have an elevated HDL-C

level greater than the 95th percentile for age
and sex.
b. clinical manifestations include eruptive
xanthomas and recurrent bouts of
pancreatitis.
c. transmission is autosomal codominant.
d. chronic treatment includes avoidance of
alcohol and dietary fat.
Lipoprotein Structure
Outer coat: Inner core:
- Apoproteins - TG
- Phospholipids - Cholesterol ester (CE)
- Cholesterol (Unesterified)
Spherical molecules of lipids and proteins (apoproteins) =

amphipathic molecules
Lipoproteins Vary in Size and
Composition
Lipoproteins Vary in Size and
Composition
More triglycerides, bigger size
More proteins, denser molecule

Four Major Lipoprotein Classes
Cholesterol-rich Triglyceride-rich
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

Binding to LDL receptor
apoB-48
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
Functions
Some are required as structural proteins
Some are activators,
Some are recognition sites.
Dietary Lipoproteins
Endogenous
Pathway
Exogenous
Pathway
Lipoprotein Assembly :
Exogenous Pathway (Chylomicrons)
Chylomicrons
• Assembled in intestinal mucosal cells

• Lowest density
• Largest size
• Highest % of lipids and lowest % proteins
• Highest triacylglycerol (dietary origin)
• Carry dietary lipids to peripheral tissues
• Responsible for physiological milky appearance
of plasma (up to 2 hours after meal)
Exogenous Pathway
(Chylomicron
and
Chylomicron Remnants)
Apo E
mediates uptake
Endogenous Pathway (VLDL-IDL)
Endogenous Pathway (IDL-LDL)
Endogenous Pathway (LDL Uptake)
Lipoprotein Assembly
Fat Cells
VLDL
LDL-R
Lipoprotein lipase
TG
Lipoprotein lipase IDL
Peripheral LDL
tissues
CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides.
Ginsberg HN. J Clin Invest. 2000;106:453–458.
Lipoprotein Lipase
• Extracellular enzyme
• Anchored to the capillary walls of most tissues

such as adipose tissue, cardiac & skeletal
muscles by heparan sulphate
• Its synthesis & transfer to luminal surface of the

capillary is stimulated by insulin
• Activated by apoC-II
Low Density Lipoprotein Cholesterol
(LDL-C)
•LDL carries about 70% of total plasma cholesterol
•High LDL-C level is well established risk factor for

development of coronary heart disease
•The diagnosis of a primary defect is made after

secondary defect causes have been ruled out
Low Density Lipoprotein
(Bad Cholesterol)
LDL Target Levels
Reverse Cholesterol Transport (HDL)
Fat Cells
CE
VLDL HDL
CETP
TG
TG
CE CETP
IDL
LDL
CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides.

Ginsberg HN. J Clin Invest. 2000;106:453–458.
LDL
LDL
HDL
Reverse Cholesterol Transport
(HDL cholesterol)
•ALL CELLS CAN MAKE CHOLESTEROL
•ONLY HDL CAN PICK UP CHOLESTEROL FROM

PERIPHERAL TISSUES
•HDL CAN CARRY CHOLESTEROL DIRECTLY BACK TO THE

LIVER
•HDL CAN TRANSFER CHOLESTEROL ESTER INTO THE

LIVER DIRECTLY OR THROUGH OTHER LIPOPROTEINS
• ONLY THE LIVER CAN DEGRADE CHOLESTEROL

Abnormalities in lipoprotein metabolism
Type I hyperlipoproteinemia = Familial lipoprotein lipase deficiency

Due to deficiency of lipoprotein lipase or apo C-II
-> accumulate of triaryglycerol–rich lipoprotein in plasma
Type II hyperlipidemia = F. hypercholesterolemia
-familial hyperbetalipoproteinemia
deficiency of functional LDL receptors
-> elevation of plasma cholesterol but plasma TG remains normal
There is premature atherosclerosis
Type III hyperlipoteinemia
= F. dysbetalipoproteinemia or broad B disease
Deficiency of apo E
-> accumulation of chylomicron remnants in plasma .
There is hyperchloesterolemia with premature atherosclerosis

Type II hyperlipidemia = Familial hypercholesterolemia
Deficiency of apo E
Metabolic defects in familial hypercholesterolemia
Decreased IDL
uptake
Increased
conversion to
LDL
50% inc
production rate
of VLDL apoB
Decreased IDL
uptake
Increased
conversion to
LDL
Prolonged LDL
residence time
Decreased IDL
uptake
Increased
conversion to
LDL
Familial Hypercholesterolemia
• Philippine prevalence (2005)
• Part of a global intiative (MedPed)
• identified 60 suspected subjects based on the
Dutch Lipid Clinic Network Criteria
• mean LDL-C was 275 mg/dL and mean FH score was
9.5
• DNA analysis for LDLR gene mutation
• 20% of the subjects were identified to have LDLR
gene mutations with 6 of these being novel
mutations
Punzalan FE at al., Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia J Atheroscler
Thromb. 2005;12(5):276-83
Punzalan FE at al., Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia J Atheroscler
Thromb. 2005;12(5):276-83
Mechanism of Proprotein Convertase
Subtilisin Kexin 9 inhibition
• “chaperones” the LDL receptor into

the cell for degradation and recycling
Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid
Res.2012;53(12):2515–24.
Mechanism of Proprotein Convertase
Subtilisin Kexin 9 inhibition
• “chaperones” the LDL receptor into • LDL-receptor is recycled back to the

the cell for degradation and recycling surface where it can again bind ApoB
particles
Res.2012;53(12):2515–24.
Gain of Function of PCSK9 mutation can
cause FH (Type II hyperlipidemia)
• “chaperones” the LDL receptor into • LDL-receptor is recycled back to the

the cell for degradation and recycling surface where it can again bind ApoB
particles
Res.2012;53(12):2515–24.

Type II hyperlipidemia = Familial hypercholesterolemia
Deficiency of apo E
Abetalipoproteinemia
defective triacyglycerol transfer protein
No chylomicrons  ↓TG& ↑ TG in small intestine & liver
No VLDL
No VLDL  no LDL  ↓ cholesterol
Hypobetalipoproteinanemia
↓ apo B-100 synthesis
↓ VLDL  ↓ TG & ↑ TG in liver
↓ LDL  ↓ cholesterol
Fatty liver : imbalance between hepatic TG synthesis & secretion of VLDL

Causes . hepatitis ,DM, chronic ethanol ingestion
Adriel E. Guerrero, M.D.
2015 Updated Chairman, Philippine Heart Association
Council on Preventive Cardiology
Clinical Practice Louella Gonzalez-Santos, M.D.
Guidelines for the Chair, Technical Research Committee
Management of Imelda V. Caole-Ang, M.D.

Jude Erric L. Cinco, M.D.
Dyslipidemia in Cecilia A. Jimeno, M.D.
Elmer Jasper B. Llanes, M.D.
the Philippines Raymond V. Oliva, M.D.
Deborah Ignacia D. Ona, M.D.
Noemi S. Pestaño, M.D.
Members, Technical Research Committee
Felix Eduardo R. Punzalan, M.D.

Facilitator to the Technical Research
Committee
International and Local Guidelines Recommend
LDL-C as the Primary Target of Therapy and
Statins as First-Line Drug
ATP III PHIL CPG ESC/EAS ACC/AHA ADA

Update (2005) (2011) (2013) (2015)
(2004)
Primary LDL-C LDL-C LDL-C LDL-C LDL-C

Target
Secondar HDL-C, Tg HDL, Non-HDL- HDL-C and

y Target/s and Non- Silent on C, ApoB Tg, Apo B
HDL Tg
Phil. CPG on Dyslipidemia, NCEP, ESC/EAS 2011, ACC/AHA 2013, 2015 ADA Standards of
Care
2011 ESC/EAS Guidelines for Dyslipidemia Management
LDL-C Non–HDL-C Apo B
Primary Target Optional Targets
Very High Risk
•Documented CVD, previous MI, ACS,
coronary or other arterial revascularization,
ischemic stroke, PAD < 70 mg/dL < 100 mg/dL < 80 mg/dL
•T2DM or T1DM with target organ damage
•Moderate to severe CKD
•Calculated 10 year risk SCORE ≥10%
High Risk
•Markedly elevated single risk factors such
as familial dyslipidemias and severe < 100 mg/dL < 130 mg/dL < 100 mg/dL
hypertension
•Calculated SCORE ≥5% and <10%
Moderate Risk
< 115 mg/dL < 145 mg/dL Not defined
•SCORE is ≥1% and <5% at 10 years
ESC/EAS Guidelines for the Management of Dyslipidemias.European Heart Journal 2011; 32: 1769-1818.
2013 ACC/AHA Guidelines to Reduce ASCVD Risk in Adults
No specific LDL-C targets but anticipated response:

High-intensity statin: ≥ 50% reduction in LDL-C
Stone NJ et al. Circulation 2013; 00: 000-000. Moderate-intensity statin: 30%-50% reduction in LDL-C
2015 ADA Standards of Medical Care:
Dyslipidemia Management
Age Risk Factors Recommended Monitoring with
Statin Dose* lipid panel
< 40 years None None Annually or as
CVD risk factors** Moderate or High needed to monitor
Overt CVD*** High adherence
40-75 years None Moderate As needed to
CVD risk factors High monitor
Overt CVD High adherence
> 75 years None Moderate As needed to
CVD risk factors Moderate or High monitor
Overt CVD High adherence
*In addition to lifestyle therapy.

**CVD risk factors include LDL cholesterol > 100 mg/dL, high blood pressure, smoking, and
overweight and obesity.
***Overt CVD includes those with previous cardiovascular events or acute coronary syndromes.
2015 ADA Standards of Medical Care. Diabetes care 2015;38:Supplement 1.

RESULTS OF THE 2013 8TH NATIONAL NUTRITION SURVEY (NNS)
RESULTS OF THE 2013 8TH NATIONAL NUTRITION SURVEY (NNS)
Mean Lipid Values Among Filipinos in the
Last 3 National Nutrition Surveys (NNS)
Lipid Mean Value (mg/dL)

Parameter 1998* 2003** 2008** 2013
Total 159 ± 1.2 184.4 186.8 201
Cholesterol
LDL-C 107 ± 1.1 119.4 118.3 131.2
HDL-C 30 ± 0.4 41.4 40.1
Triglyceride 116 ± 1.9 118.0 141.3 154.4
s
*capillary blood, desktop analyzer

**venous blood, central laboratory
FNRI DOST National Nutrition Survey 1998, 2003, 2008.

GRADE PRO Summary of Findings
Table Quality of
Evidence Clinical
High Quality of Evidence + Critical outcome
Outcome = Strongly Recommend
Recommendations
Quality of Outcome NNT Recommendation
Evidence
High Critical Low Strongly
Recommend
Moderate Critical Low Recommend
Moderate Important Low May

Recommend
Low Critical High or NS Do not
recommend
2015 Updated Clinical Practice Guidelines for the
Management of Dyslipidemia in the Philippines
Statement 1.1 Diet

For individuals at any level of cardiovascular risk, especially
those with established atherosclerotic cardiovascular
disease (ASCVD), a low- fat, low cholesterol diet, rich in
fruits and vegetables, is RECOMMENDED.
Statement 1.2 Smoking Cessation

For individuals at any level of cardiovascular risk, cigarette
smoking cessation is STRONGLY RECOMMENDED.
Statement 1.3. Exercise

For individuals at any level of cardiovascular risk, adequate
exercise is RECOMMENDED.
Statement 2
For non-diabetic individuals aged ≥ 45 years with
LDL-C ≥ 130 mg/ dL AND ≥ 2 risk factors*, without
atherosclerotic cardiovascular disease, statins are
RECOMMENDED for the prevention of
cardiovascular events.
*Risk factors are: male sex, postmenopausal women, smoker,
hypertension, BMI > 25 kg/m2, family history of premature CHD,
microalbuminuria, proteinuria, and left ventricular hypertrophy.
*Patients who fulfill the criteria for the diagnosis of familial
hypercholesterolemia (see statement 6 on screening and lipid
monitoring for familial hypercholesterolemia) should be initiated
therapy for aggressive LDL-C lowering
Statement 3
For diabetic individuals without evidence
of atherosclerosis (ASCVD), statins are
RECOMMENDED for primary prevention of
2015 TRC Clinical Questions
Non-statin Therapy
Clinical Question 4:
Among diabetic patients without ASCVD, should
fibrates be recommended as an alternative to statin
therapy?
Clinical Question 6
Among patients with ASCVD, should fibrates be given
as an alternative to statins?
Clinical Question 9
Among patients with ASCVD, should omega-fatty acids
be given as an alternative to statin treatment?
STATEMENT 5
For individuals with atherosclerotic

cardiovascular disease (ASCVD), statin therapy
is recommended
RECOMMEND
Statements 7
For individuals with evidence of ACSVD or diabetes, the

use of the lipid profile is RECOMMENDED for monitoring
of treatment response since ALL patients with ASCVD
should be on lipid-lowering therapy.
For individuals without evidence of ASCVD but aged > 45

years AND with 2 or more risk factors*, the use of lipid
profile for screening is RECOMMENDED.
For individuals on lipid-lowering therapy, the use of lipid

profile for monitoring of treatment response is
RECOMMENDED.
Statement 8
For individuals with acute coronary

syndrome, early high-intensity statin
therapy is RECOMMENDED and should
be continued when already on statin
therapy.
Non-statin Therapy
therapy?
Clinical Question 6
Clinical Question 9
Non-statin Therapy
therapy?
For diabetic individuals without evidence of

ASCVD, fibrates are NOT RECOMMENDED as an
alternative to statin for the primary prevention
of cardiovascular events.
Non-statin Therapy
Clinical Question 6
Among patients with established ASCVD,

fibrates are NOT RECOMMENDED as an
alternative to statins.
Non-statin Therapy
Clinical Question 9
For patients with evidence of ASCVD, poly-

unsaturated fatty acid (PUFA) or omega 3 fatty
acid is NOT RECOMMENDED as an alternative to
statins for the secondary prevention of
Non-statin Therapy
Combination Therapies
• combination therapy of a non-statin therapy (eg: omega 3
FA, ezetimibe, fibrates) and a statin may allow for a
greater degree of LDL-C reduction
Screening and treatment algorithm for the
management of dyslipidemia
Algorithm for Patients who are on Statins
with Elevated Liver Enzymes
Algorithm for Statin-Induced Myopathy
1. VLDL particles
a. contain apo B48 as their main

lipoprotein.
b. acquire apo C’s and apo E.
c. exchange cholesteryl esters for
triglycerides from HDL.
d. are larger than chylomicrons.
2. Reverse cholesterol transport pathway
a. occurs in the intestinal pathway.

b. constitutes transfer of phospholipids onto
nascent HDL particles mediated by
lipoprotein lipase (LPL).
c. facilitates transfer of cholesterol from
HDL to VLDL remnants so that it can be
metabolized in the liver.
d. involves a unidirectional transfer of
constituents between lipoproteins.
3. True of LDL particles
a. Each LDL particle contain several molecule

of apo B.
b. LDL-R is localized in a region of the plasma
membrane rich in the protein cathepsin.
c. Normally triglycerides constitute only 4%
to 8% of the LDL mass.
d. A relative increase in cholesteryl esters
leads to smaller, denser LDL particles.
4. High density lipoprotein
a. contains apo A-I, the main protein of

HDL, synthesized by the intestine and liver.
b. precursors, called nascent HDL, are
easily measured in the fasting lipid profile.
c. provides cholesterol to steroid
hormone– producing tissues and the liver
through the scavenger receptor SR-B1.
d. All of the above are true.
5. In type II hyperlipidemia
a. affected subjects have an elevated HDL-C

level greater than the 95th percentile for age
and sex.
b. clinical manifestations include eruptive
xanthomas and recurrent bouts of
pancreatitis.
c. transmission is autosomal codominant.
d. chronic treatment includes avoidance of
alcohol and dietary fat.
Overview of Lipid, Apolipoprotein and
Lipoprotein
Lipid Metabolism and the 2015
compounds:
Updated CPG
Relatively in insoluble
water the Management of
Dyslipidemia in the Philippineslasma
Therefore, (aqueous) as Lipoprot in eins
they are transported
Lourdes Ella G. Santos, MD
Dyslipidemia
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

7 Overview of Lipid

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7 Overview of Lipid

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Overview of Lipid, Apolipoprotein and

a. contain apo B48 as their main

a. occurs in the intestinal pathway.

a. Each LDL particle contain several molecule

a. contains apo A-I, the main protein of

a. affected subjects have an elevated HDL-C

Spherical molecules of lipids and proteins (apoproteins) =

More triglycerides, bigger size

More proteins, denser molecule

apoA-IV Tg metabolism; LCAT activator; diet response

apoB-100 Structural protein of all LP except HDL

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

• Assembled in intestinal mucosal cells

Lipoprotein lipase IDL

• Anchored to the capillary walls of most tissues

• Its synthesis & transfer to luminal surface of the

•LDL carries about 70% of total plasma cholesterol

•High LDL-C level is well established risk factor for

•The diagnosis of a primary defect is made after

CE, cholesteryl esters; FFA, free fatty acids; TG, triglycerides.

•ALL CELLS CAN MAKE CHOLESTEROL

•ONLY HDL CAN PICK UP CHOLESTEROL FROM

•HDL CAN CARRY CHOLESTEROL DIRECTLY BACK TO THE

•HDL CAN TRANSFER CHOLESTEROL ESTER INTO THE

• ONLY THE LIVER CAN DEGRADE CHOLESTEROL

Type I hyperlipoproteinemia = Familial lipoprotein lipase deficiency

Type I hyperlipoproteinemia = Familial lipoprotein lipase deficiency

• “chaperones” the LDL receptor into

• “chaperones” the LDL receptor into • LDL-receptor is recycled back to the

• “chaperones” the LDL receptor into • LDL-receptor is recycled back to the

Type I hyperlipoproteinemia = Familial lipoprotein lipase deficiency

Fatty liver : imbalance between hepatic TG synthesis & secretion of VLDL

Management of Imelda V. Caole-Ang, M.D.

Felix Eduardo R. Punzalan, M.D.

ATP III PHIL CPG ESC/EAS ACC/AHA ADA

Primary LDL-C LDL-C LDL-C LDL-C LDL-C

Secondar HDL-C, Tg HDL, Non-HDL- HDL-C and

No specific LDL-C targets but anticipated response:

*In addition to lifestyle therapy.

2015 ADA Standards of Medical Care. Diabetes care 2015;38:Supplement 1.

Lipid Mean Value (mg/dL)

*capillary blood, desktop analyzer

FNRI DOST National Nutrition Survey 1998, 2003, 2008.

Moderate Critical Low Recommend

Moderate Important Low May

Statement 1.1 Diet

Statement 1.2 Smoking Cessation

Statement 1.3. Exercise

For individuals with atherosclerotic

For individuals with evidence of ACSVD or diabetes, the

For individuals without evidence of ASCVD but aged > 45

For individuals on lipid-lowering therapy, the use of lipid

For individuals with acute coronary

For diabetic individuals without evidence of

Among patients with established ASCVD,

For patients with evidence of ASCVD, poly-

a. contain apo B48 as their main

a. occurs in the intestinal pathway.

a. Each LDL particle contain several molecule

a. contains apo A-I, the main protein of

a. affected subjects have an elevated HDL-C

apoE B/E receptor ligand E2:IDL; E4: Diet Responsivity