lipid metabolism using transporters,receptors and enzymes.drugs usedin dyslipidemia

1. Cholesterol metabolism//
Dyslipidemia managment
BY
Mohie-Aldien A Sherif
Professor of Pharmacology, Faculty of Medicine, Benha University,
Benha, Egypt

2. 1)Triglycerides(TG):*<150upto200mg/dL*Source:sugars,alcohol
*ProvidesEssentialenergysourceandstorage
*Carriedinbloodby:1-chylmicroninportalcirculation.
2-Verylow-densitylipoprotein(VLDL)insystemiccirculation
2)Freefattyacids(FFA)
*Source:triglyceride
*Carriedinbloodbyalbumin
Glycerol
Three
Fatty
Acids
Lipids

3. Lipoproteins (LP)
•Lipids need to get to site of action for
use but not water-soluble / not readily
carried by bloodstream. Thus:
• Special transport “vehicle” necessary
for delivery of lipids to tissues for use
(LP is the carrier of TG and C).
LP Consist of:
1- Wall: consist of phospholipids and some
free C.
2- Core: at which TG /Ch are stored.
3- Apolipoproteins (Apo): regulate LP
metabolism
3) Cholesterol (C): * Source: fats, dietary cholesterol
*Essential for Bile acid, steroid hormone & Cell membrane synthesis. Cell growth,
cell division,
*Carrier in blood:
1-Low-density lipoprotein (LDL): transports C from liver to peripheral tissue.
2-High-density lipoprotein (HDL): transfer C from peripheral tissue to liver.

4. CM (VLDL) IDL LDL HDL
Diamete 75-1200(µm) 30 -80(µm) 25-35 (µm) 18-25 5-18
Apo B48 ,E,A1,C I,II,III B100, E, CI/II/III B100,E ,CII/III B100 AI/II/IV/V;CI/II/III , E
TG /C 85% 55% /20% 25% / 35% 5% /60% 5% /20%
Function Transport
exogenous TG, Ch
in portal circulation
TG & Ch
transport in
systemic
circulation
TG & Ch.
transport
Ch. transport from liver
to peripheral tissue
1- Larger LDL
(less atherogenic)
2- Small dense LDL
(sd.LDL),More
atherogenic
1- transfer Ch from
peripheral tissue to
liver
.2-Transfer &
recycling of Apo
between LPs
3-Antiinfalmation
4-antioxidant
Formed
from
Nascent CM in
blood (ApoB48) +
Apo C & E derived
from HDL
Formed in the
liver
VLDL remnant IDL by removal of ApoE
by LCAT
Nascent HDL from
liver (ApoA, C, A)
+CE
Fate FA& Glycerol
- CM Remnants
(Cleared by liver)
IDL LDL (Cleared
by LDL
receptor
Removed from blood via
LDL receptors
HDL2 by LCAT
(Cleared in liver by
scavenger receptor
class BI.
B48
E
A
TG
B100
E
B100
E
B100
B100
Types of lipoproteins (LP):
A

5. LDL
Lipoprotein
lipase
Capillary wall
(endothelial surface)
Tissues
This animation shows how VLDL are metabolised once
they enter the circulation from the liver
VLDL
B100
CII
E
B100
Some LDL taken up
by liver (LDL receptors)
Some LDL taken up by
other tissues (LDL receptors).
LDL delivers cholesterol and
TAG to the extra hepatic tissues.
Having lost TAG to tissues
LDL contains a large
proportion of
cholesterol/cholesterol
esters

7. Type Associated Lp Function
B48 Chylmicron Export of chylomicrons from intestinal cells,
Lacks LDL receptor binding domain
B100 VLDL, IDL, LDL LDL receptor legend
C-II Chylmicron. VLDL, IDL, HDL LPL activator
C-III Chylmicron. VLDL, IDL, HDL
(its production ↓ by fibrate ,pioglitazone)
-Inhibits LPL
-Inhibits ApoB binding to LDL receptor
C-I Chylmicron. Activate LPL & LCAT
E Chylmicron. VLDL, IDL, HDL Legend, LDL receptor, LRP receptor → clears
remnants , IDL, and HDL
A-1 HDL / Chylomicron Activates LCAT & ABAC1 transporter
A-II HDL Form s-S with apoE2,3→ inhibit binding to receptors
enhances hepatic lipase activity?
A-V Activate LPL , modulate TG incorporation into VLDL
Lp (a) differs from LDL by the
additional presence of (a) covalently
bound to apo B by disulfide bridge
Independent risk factor for IHD .Structural similarity to
plasminogen, thus interfering with fibrinolysis &promotes
atherogenesis and thrombosis.
Disulp-
hide
bridge
B100
a
Lower Lp(a) :Niacin; Estrogen;Fenofibrate?; Extra LDL-C lowering

8. Lp(a)—Summary
• Pro-atherogenic/pro-thrombotic factor
• Genetically determined
• Not lowered by most treatments:
–Diet
–Exercise
–Weight loss
–Statins,
–Bile acid resins,
–Gemfibrozil
• Rx options:
–Lower Lp(a)
• Niacin
• Estrogen
• Fenofibrate?
–Extra LDL-C lowering

9. Transporters Function
Cholesterol
ester transfer
protein
(CETP) .
Site: Blood
Transfer C from HDL to
other lipoproteins in
exchange for TG
(VLDL)Which becomes
heavier and becomes
IDL& LDL).
ATP-binding
cassette A1
(ABCA1)
Site: Cell
membrane
translocation Ch across
the plasma membrane to
nascent HDL &
presenting them to ApoA-
I, which binds to/activate
ABCA1
ATP-binding
cassette
transporter G1
(ABCG1)
promotes ch efflux from
cells to mature HDL
particles & regulates
intracellular cholesterol
homeostasis
1-NPCILI
2-ABCG5/G8
Site: Cell
membrane
(enterocyte)
1-cholesterol/sterol influx
in enterocyte
2-Sterols other than
cholesterol are
transported back into the
intestinal lumen
HDL
Apo B
Ch Ester
TG
or Chylomicron
Remnant
Apo AI
Apo E
VLDL
CETP
apoA-I
Nascent HDL
Nieman-Pick C1-Like 1 (NPC1L1) channel

10. Transporters Site Function
Microsomal TG
Transfer Protein
(MTP)
Intestine,
liver
(SER/Golgi
apparatus))
Loads TGs,ChE
onto B48 (gut) and
B100 (liver
I) Organic anion
transport protein
(OATP-c)
II)
*P. glycoprotein
*Multidrug
resistance
associated protein
(MRP)
I) Cell
membrane.
II) Cell
membrane.
I) Influx: Transport
statin inside cells
(Intestine, liver,
kidney, brain)
II) Efflux (to
bile):
1- Transport statin
outside cells
(Intestine, liver,
kidney, brain)
2- Transport
hydrophilic statin
outside cells
(Skeletal muscle ,
Intestine, liver,
kidney, brain)
Cont.

11. Enzyme Site Modulators Function
Lipoprotein lipase
(LPL)
Capillary
walls
↑By apo CII & apo CIII,
ANGPTL3
Excises FFA from TG in CM& VLDLs at fed
stage for adipose and muscle
HSL:Hormone-
sensitive Lipase
Inside
cells
( insulin) &( gluca-gon,
adrenaline , cAMP)
mobilization of FFA from the TG (adipose
tissue at fasting state.)
ACAT=Acyl-CoA
cholesterol
acyltransferase
Inside
cells
 By Free C. Intracellular Ch. estererfication for storage
LCAT=lecithin
ch.acyltransferase
Blood
(HDL).
By apo A1 1- C. esterification to be carried by HDL.
2- IDL  LDL by removal of ApoE
angiopoietin-like
protein 3 4
Blood,
liver
↓ by evinacumab - ↓LPL,LDL receptor expression→ ↑ LDL ,TG
-↓endothelial lipase →↓HDL

12. Transporter Site Function
Cholesterol ester transfer
protein (CETP)
Blood Transfer C. from HDL to other Lp in exchange for TG (VLDL Which
becomes heavier and becomes IDL& LDL).
Cholesterol ester Reverse
protein (CERP)
Plasma membrane -Activated by apo A1
-Flips C. & lecithin to outer layer of lipid bilayer for LCAT action
Microsomal Triglyceride
Transfer Protein (MTP)
Intracellular
(Intestine, liver)
Loads TGs onto B48 (gut) to form chylmicron and B100 (liver) to form
VLDL.
ATP-binding cassette A1
(ABCA1)
Cell membrane translocating C across the plasma membrane bilayer and presenting them to
ApoA-I, which binds to ABCA1
ABCG5/G8 Intracellular Intestine: Sterols other than cholesterol are transported back into the
intestinal lumen.
Proprotein convertase
Subtilisin /Kexin Type 9
(PCSK9)
blood bind to LDL-receptor complex→ endocytosis→↑LDL receptor degradation
→↓LDL receptor at cell membrane →↑LDL.C in blood
PCSK9

13. Receptors ligand Results of activation
LDL (B/E )
receptor
ApoB100
/ ApoE
Uptake CM-remnant,
LDL, IDL, VLDL to
deliver C
scavenger
receptor
(SRB1)
ApoA1 HDL uptake by
Hepatocyte
LOX/
scavenger
receptor/
(SRA1 ,
CD36 ,
/LRPB1 )
Oxidized
LDL
(B-100 loss
by ROS)
Endothelium
dysfunction, Monocyte
attachment &activation
& LDL uptake by
macrophage
*PPAR-α fibrates 1-ABCA1 gene
transcription
2-ApoA1&Apo All
expression   Nascent
HDL
3- Apo CIII expression
LPL
(Peroxisome pro-liferator Activated Receptor α)

14. (54 mg/dl)
(303 mg/dl)
(253 mg/dl)
(870 mg/dl)
All values are mg/dL
Pediatrics 2008;122:198–208
Adult Children/adolecent
Total cholesterol
<200 Desirable < 170 mg/dL
200–239 Borderline high 170-199 mg/dL
240 High 200 mg/dL
LDL cholesterol
<100 Optimal
100–129 Near or above
optimal
< 110 mg/dL
130–159 Borderline high 110-129 mg/dL
160–189 High > 130 mg/dL
190 Very high
HDL cholesterol
<40 Low < 35 mg/dL
60 mg/dL High
Triglycerides
<150 Normal
150–199 Borderline high
200–499 High > 150 mg/dL
500 Very high

16. Secondary hyperlipidemias
Disorder VLDL LDL HDL Mechanism
Diabetes mellitus ↑ ↑ ↑ ↑ ↓ VLDL production ↑,LPL ↓, altered LDL
Hypothyreosis ↑ ↑ ↑ ↑ ↓ LDL-rec.↓, LPL ↓
Obesity ↑ ↑ ↑ ↓ VLDL production ↑
Anorexia - ↑ ↑ - bile secretion ↓, LDL catab. ↓
Nephrotic sy ↑ ↑ ↑ ↑ ↑ ↓ Apo B-100 ↑ LPL ↓ LDL-rec. ↓
Uremia, dialysis ↑ ↑ ↑ - ↓ LPL ↓, HTGL ↓ (inhibitors ↑)
Pregnancy ↑↑ ↑ ↑ ↑ oestrogen ↑;VLDL production ↑, LPL ↓
Biliary obstruction - - ↓ Lp-X ↑ ↑,no CAD; xanthomas
Alcohol ↑↑chylom. - ↑ dep. on dose, diet, genetics
Many-many drugs
Alcohol (↑VLDL, ↑HDL); Estrogens (↑VLDL , ↓LDL, ↑ HDL); Anabolic androgens (↑LDL,
↓HDL); Cyclosporin (↑LDL);Thiazide diuretics (↑LDL, ↑VLDL.) ;Beta-blockers (↑VLDL,
↓HDL).glucocorticoid (↑VLDL,LDL).

19. Natl Sci Rev. 2014;2(1):85-99.
(Muscle
pain)
ATP-citrate Lyase (ACL) Bompedic acid
↓NOS, tPA, ↑thrombosis,PAI-1,cellular migration and
proliferation, cytosolic production and adhesion molecules
TCA cycle (tricarboxylic acid cycle)

20. Bile
salts
TG,
C
Lipase
Mixed micelle
(200– 500 mg of ch/day)
(800–1200 Chmg /day)
Enterocyst
B48
E
A
B48
E
FFA LPL
LRP
SR-BI
Portal circulation
AI/AII
E
HDL
I) Exogenous Lipid Transport

22. Apolipoprotein B-containing lipoproteins that cause cardiovascular disease
Nordestgaard, B. G. et al. (2018) Advances in lipid-lowering therapy through gene-silencing technologies
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2018.3
Grey arrows indicate targets for reducing plasma levels of various lipoproteins using gene-
silencing approaches. ANGPTL3, angiopoietin-related protein 3; apo(a), apolipoprotein(a); apoB,
apolipoprotein B; apoC3, apolipoprotein C3; Lp(a), lipoprotein(a).

23. Mixed
micell
e
sterol
NPCILI ABC5 /G8
LRP
Stable Plaque
(Thick fibrous cap)
B48
E
A
B48
E
FFA LPL
MTP
TG
B100
E
VLDL
B100
Large LDL
(Low atherogenic)
B100
E
IDL
B100
sLDL
(High atherogenic)
Monocyte
MCP-1
Macrophage
Cytokines/
GFs
Inflammation
CETP
LCAT
ABCA1
Pre-B HDL
A-I
A
PON1
A-I
Lipid free A1
A-I
spherical small,
dense HDL3
CERB
large, light HDL2
A
PON1
LCAT
SR-BI
Un-Stable
Plaque
(Thin / rupture fibrous cap &
thrombus)
Pre-B HDL
A-I
Pre-B HDL
A-I
Ezetinib

24. Expansion overcome:
lumen narrows
Advanced
CAD
Moderate
CAD
Compensatory expansion
maintains constant lumen
Minimal
CAD
Glagov’s Remodelling Hypothesis
Progression
Glagov S, et al. N Engl J Med. (1987) 316:1371-1375.
Normal vessel/
endothelial
dysfunction
healthy
Decades
Decades/Years
Minutes
ACS

25. Parameter Small molecules Antibodies Gene silencing
ASO small interfering RNA
structure Organic compound Protein Single-stranded RNA Double-stranded RNA
Mass (kDa) <1 ∼150 ∼12 ∼21
Mechanism Blocks enzyme /receptor in
cells
Blocks protein in plasma Blocks gene mRNA
transcripts in cell
Blocks gene mRNA
transcripts in cell
adverse effects High (non-tissue-specific
effects)
Low( high target
specificity )
Low( high
specificity)
Low, high specificity)
Immunogenicity Low High High High
Efficacy ↓50% LDL-c ↓60% LDL-c ↓90% LPa ↓50% LDL-c
drug response High High Low Low
Half-life Days Weeks Months >1 year
frequency/ rout Oral /Daily SC weekly , twice/month SC /Monthly SC / Twice yearly
Targets Proteins in ng to µg Proteins in µg - mg Lipoproteins in g Lipoproteins in g
example •Statins (↓HMGco A)
•Ezetimib (NPC1L1)
•Pemafibrate > Fibrates (↑
PPAR- →↓TG)
• Omega-3 fish oil, Niacin
(↓Diacyl glycerol Acyl Transferase
→ ↓TG .
•Icosapent ethyl, a highly
purified eicosapentaenoic
acid ethyl ester→ ↓TG
•Lomitapide (↓ MTP) → ↓TG
•Bempedoic acid(↓ATCL)
•Evolocumab ;
alirocumab: (PCSK9)
inhibitors .
•evinacumab =
ANGPTL3) inhibitor =
↓TG, LDLc
• mipomersin
(↓ApoB
(for HoFH, ↓TG).
•Volanesorsen (↓Apo
C3 for familial
chylimicro-nemia
syndrome.
•AKCEA-APO(a)-LRx
(↓Lpa )
•Small interference RNA
against PCSK9
(inclisiran) →non-HDL,
apoB and Lp(a) 25%,

26. Bioactive properties of Icosapent Ethyl and its effects of gene expression, arterial stiffness,
atherogenic lipids, and plaque volume
modest reduction in TG
(~ 20%), a 25% relative
risk reduction in the
primary endpoint and a
30% reduction in total
events.
Sub-analysis of REDUCE-
IT also showed a statically
significant decrease in
cardiac arrest (HR 0.52
(0.31-0.86), p = 0.01) and
sudden cardiac death (HR
0.69 (0.50-0.96), p =
0.03).

27. canakinumab : an
interleukin-1-beta
inhibitor
Abbreviations: SQ,
subcutaneous. FH,
familial
hypercholesterolemia.
siRNA, small interfering
RNA. ANGPTL3,
angiopoietin-like protein
3. UTI, urinary tract
infection. TG,
triglycerides. Plt,
platelets. FCS, familial
chylomicronemia
syndrome. PPAR-alpha,
peroxisome proliferator
activated receptor
alpha. CK, creatine
kinase. Cr, creatinine.
ALT, alanine
aminotransferase. ASO,
antisense
oligonucleotide..

28. Summary of novel preventive therapies organized by mechanism .
canakinumab : an interleukin-
1-beta inhibitor
(GLP-1 receptor
agonists)
Approved-Pre-beta HDL
is a lipid-depleted form of
HDL with high efficacy in
clearing cholesterol from
lipid-laden macrophages.
The plasma delipidation
system (PDS-2, HDL
Therapeutics), converts
an individual’s native HDL
into pre-beta HDL.
Autologous transfusion of
highly concentrated pre-
beta HDL then mediates
clearance of cholesterol
from existing in low-
density and necrotic
plaques, which are most
associated with future
fatal and nonfatal MI-
in homozygous FH.
CRISPR-Cas9 restores function
in the LDL receptor among
mice with a common FH
mutation. Significant
reductions occurred in plasma
lipid levels with concomitant
reductions in atheromatous
plaque on gross specimens.
Ch.clearance-from-
macrohage(Pre-beta HDL)

29. Robert A. Hegele. Circulation Research. Lipid-Lowering Agents, Volume: 124, Issue: 3, Pages: 386-404, DOI: (10.1161/CIRCRESAHA.118.313171)

30. Nordestgaard, B. G. et al. (2018) Advances in lipid-lowering therapy through gene-silencing technologies
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2018.3
Efficacy of different
approaches to lipid
lowering
(Evolocumab ; alirocumab)
2SC/Y
Lomitapide (↓ MTP)
(↑FFA oxidation
/↑LDL diameter)

31. ATP-citrate Lyase (ACL) Bompedic acid
↓NOS, tPA, ↑thrombosis,PAI-1,cellular migration and
proliferation, cytosolic production and adhesion molecules
(Muscle pain)
Natl Sci Rev. 2014;2(1):85-99.
TCA cycle (tricarboxylic
acid cycle)

32. Natalie C. Ward. Circulation Research. Statin Toxicity, Volume: 124, Issue: 2, Pages: 328-350, DOI: (10.1161/CIRCRESAHA.118.312782)
mechanisms for the development of statin toxicity. FPP = farnesyl
pyrophosphate; GGPP=geranylgeranyl pyrophosphate; GPP, =geranyl pyrophosphate;

33. Natalie C. Ward. Circulation Research. Statin Toxicity, Volume: 124,
Issue: 2, Pages: 328-350, DOI: (10.1161/CIRCRESAHA.118.312782)

36. Statins Bempedoic acid Ezitimib Fibrates BA
sequestrants
Nicotinic acid Omega-3 fish oil Lomitipid
Mechanis
m
↓intracellular hepatic
ch (HMG CoA) →↑
LDL -R
expression→ ↑
uptake of non-HDL
*LDL c ( 24–50% );
TG ( 10–29%);
HDL c ( 6–12% )
↓ ATP citrate
lyase / ↑ AMPK
(adjunct to diet
and maximally
tolera-ted statin
for adults with
hetero-zygous
familial hyper-
cholesterolemia or
atherosclerosis
need extra- lower
ing of LDL-C.
 Nieman-
Pick CI-
Like 1
(NPCIL1)
channel
  C
intestinal
absorption
(not used
alone)
*LDL..c
18%
↑ PPAR-:
* Apo CIII
 ↑LPL →
clearance of
TG-rich
lipoproteins
*↑ Apo-AI/II
 ↑HDL
*↓coagulation.
↑ fibrinolysis
*TG ( 20–
50%)
BA reabsorbion
 Up regulation
of LDL receptor
& ↑ the uptake of
non-HDL from
circulation.
*LDL c ( 15–
30% );
*↓Diacyl Glycerol
Acyl Transferase →
↓TG→  VLDL and
apo B.
*TG (20–50%);
HDL c ( 15–30% )
↓ TG; membrane
Ch. crystalline
domains, oxLDL,
Adhesion of
monocytes,
Macrophages
Foam cells.
Anti-
inflammatory
microsomal
triglyceride
transfer protein
inhibitor in GIT&
liver;
used in Adult
patients with
homozygous
familial
hypercholest-
erolemia (HoFH)
Toxicity rhabdo-myo lysis (<
0.1 % ) myalgias
reversible, myopathy,
↑ hepatic transamin-
ases ( dose dependent
),Dyspepsia /
Tendon rupture,
hyperuricemia,
back pain,
bronchitis, pain in
extremity, anemia,
and ↑ liver
enzymes
Only 20%
absorption
so lower
side-effect
profile
Nausea,
diarrhea,
cholelithiasis,
phototoxicity
Constipation,
bloating,
abdominal pain,
unpleasant taste
and texture.
Liver toxicity,
jaundice, Dyspepsia
Flushing, warmth
(PGD2 &E2) , rashes
Pruritus, , ,acanthosis
nigricans ,flu like
fatigue, hyper-
glycemia , Hyper
uricemia , ↑ statins
myopathy.
A fishy taste
in mouth
Fishy breath
Stomach upset
Loose stools
ausea,
arrhythmias, ↑
liver enzymes
Steatohepatitis ,
GIT upset,
↑ transaminases
protection Yes (CV) No Yes(CV) Yes (high TG) No No Yes (CV) No
Contraind
ications
liver disease,
pregnancy &
lactation
Pregnancy,
lactation
-------------- Children &
pregnant
women •
Renal failur
TG >200mg/dl;
dysbetalipoprotei
n emia
Peptic ulcer ; DM
Gout; Pregnancy
pregnancy
category
C.breast feeding
Pregnancy,
nursing, pediatric,
liver impairment,
active liver
disease,
Drug
Interact-
ions
• Lova.,Simva.>
Atorva( dependent on
CYP3A4)
• Lova & Simva-
statin
(contraindicated with
protease inhibitors)
↑ toxicity with
statin
------------- •Protein
binding
displacement
(Warfarin)
•May interfere
with absorption
of other
medications
•Alcohol  hepato-
toxicity risk
• Statins, fibrates 
hepatotoxicity/
myalgias .
Orlistat ↓
absorption,
Contraceptives
↓efficacy,↑ BP
lowerin with
antihypertensives
CYP3A4
inhibitors, ↑
plasma level of
warfarin ;
↑myopathy risk
with statin

37. Thank you

38. Nonalcoholic
Fatty Pancreas
Disease
Nut in Clin Prac, Volume: 34, Issue: S1, Pages: S49-S56, First published: 19 September 2019, DOI: (10.1002/ncp.10397)

39. Comparisons between fatty
liver and fatty pancreas.
NAFL: non-alcoholic fatty liver;
NASH: non-alcoholic steatohepatitis;
HCC: hepatocellular carcinoma;
NAFP: non-alcoholic fatty pancreas;
NASP: non-alcoholic steatopancreatitis;
PDAC: pancreatic ductal
adenocarcinoma.

42. Strategies to inhibit ANGPLT3 to lower blood lipid levels
Rhee, J. –W. & Wu, J. C. (2018) In vivo genome editing of ANGPTL3: a therapy for atherosclerosis?
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2018.38
ApoC III
The Cas9 enzyme is directed to specific
locations in the genome by a short piece of
‘guide RNA’ and cut the DNA

43. LCAT
(-) apo CIII; ANGPLT
(+) apo CII, ApoCI

44. The diagram shows the known and putative actions of fibrates/selective peroxisome proliferator receptor α modulators
(SPPARαM); fish oils (Omega-3 FA); statins; PCSK9 inhibitors (PCSK9i).