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Focus on triglycerides
1. Focus on TriglyceridesFocus on Triglycerides
Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFC
Fellowship in Intensive Care MedicineFellowship in Intensive Care Medicine
Infection Control Fellows CourseInfection Control Fellows Course
Consultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical Care
Ivy Hospital Sector 71 MohaliIvy Hospital Sector 71 Mohali
Web:-Web:- http://www.medicinedoctorinchandigarh.comhttp://www.medicinedoctorinchandigarh.com
Mob:- +91-7508677495Mob:- +91-7508677495
2. Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation
Doi H, et al. Circulation. 2000;102:670-676; Colome C, et al. Atherosclerosis. 2000;49:295-302; Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994.
HDLHDLLDLLDLChylomicrons, VLDL, andChylomicrons, VLDL, and
their catabolic remnantstheir catabolic remnants
> 30 nm> 30 nm 20–22 nm20–22 nm
Potentially proinflammatoryPotentially proinflammatory
9–15 nm9–15 nm
Potentially anti-Potentially anti-
inflammatoryinflammatory
6. Structure of LDL and HDLStructure of LDL and HDL
Hydrophobic CoreHydrophobic Core
of Triglyceride and Cholesterylof Triglyceride and Cholesteryl
EstersEsters
LDL
Hydrophobic Core of TriglycerideHydrophobic Core of Triglyceride
and Cholesteryl Estersand Cholesteryl Esters
Surface Monolayer of Phospholipids andSurface Monolayer of Phospholipids and
Free CholesterolFree Cholesterol
Apo A-IIApo A-II
Apo A-IApo A-I
Surface Monolayer of Phospholipids andSurface Monolayer of Phospholipids and
Free CholesterolFree Cholesterol
HDL
12. Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts
CholateCholateCholesterolCholesterol
CholesterolCholesterol
77αα-hydroxylase-hydroxylase
HOHO
HOHO
OHOH
COO -COO -
OHOH
Bile salts are the breakdown products of cholesterol. Their function is to transport
cholesterol in the digestive system
17. Lipoprotein MetabolismLipoprotein Metabolism
HDL is assembled through the combination of
cholesterol, phospholipids, and apo A I, produced
in the liver and gut. Cholesterol is incorporated in
part by the action of the adenosine triphosphate-
binding cassette-1 and is then esterified by lecithin
CE transfer protein (LCAT) allowing HDL to
enlarge into spherical HDL3 and HDL2. VLDL is
secreted by the liver and processed on the vascular
endothelium by LPL. LPL is activated by apo C II
and inhibited by apo C III. CMs are secreted by the
gut. Phospholipids released by lipolysis of both
CM and VLDL contribute to the formation of small
dense pre |[beta]| or discoidal HDL and the
VLDL remnant particle is either taken up directly
by the liver through the lipoprotein-like receptor
or is transformed into LDL by action of CE transfer
protein, exchanging the CE-rich core of HDL with
VLDL TGs. CM remnants are taken up by the
liver. TG-rich HDL is then processed by HL into
smaller dense HDL. Mature HDL2 either transfers
CEs to the liver by interaction with the scavenger
receptor B-1 or transfers its CE-rich core to VLDL
remnants creating LDL. Small dense pre |[beta]|
or discoidal HDL is subject to accelerated
degradation in part by the kidney.
18. The exogenous, endogenous, and reverseThe exogenous, endogenous, and reverse
cholesterol pathways.cholesterol pathways.
The exogenous pathway transports dietary fat
from the small intestine as chylomicrons to the
periphery and the liver. The endogenous pathway
denotes the secretion of very low density
lipoprotein (VLDL) from the liver and its
catabolism to intermediate density lipoprotein
(IDL) and low-density lipoprotein (LDL).
Triglycerides are hydrolyzed from the VLDL
particle by the action of lipoprotein lipase (LPL) in
the vascular bed, yielding free fatty acids (FFAs)
for utilization and storage in muscle and adipose
tissue. High-density lipoprotein (HDL) metabolism
is responsible for the transport of excess
cholesterol from the peripheral tissues back to the
liver for excretion in the bile. Nascent HDL-3
particles derived from the liver and small intestine
are esterified to more mature HDL-2 particles by
enzyme-mediated movement of chylomicron and
VLDL into the HDL core, which is removed from
the circulation by endocytosis.
19. Endogenous Lipid MetabolismEndogenous Lipid Metabolism
• In the liver, triglycerides (TGs),
cholesteryl esters (CEs), and
apolipoprotein B100 are packaged as
very low density lipoprotein (VLDL)
particles.
• TG is hydrolyzed by lipoprotein lipase
(LPL) to generate intermediate density
lipoprotein (IDL), which is further
metabolized to generate low density
lipoprotein (LDL).
• This particle can be removed by the
liver or by peripheral cells. Cholesterol
derived from LDL regulates several
processes and can be used for the
synthesis of bile acids, steroid
hormones, and cell membranes.
24. Specific Dyslipidemias: Elevated TriglyceridesSpecific Dyslipidemias: Elevated Triglycerides
Classification of SerumClassification of Serum
TriglyceridesTriglycerides
NormalNormal <150 mg/dL<150 mg/dL
Borderline highBorderline high 150–199150–199
mg/dLmg/dL
HighHigh 200–499200–499
mg/dLmg/dL
25. Causes of Elevated TriglyceridesCauses of Elevated Triglycerides
Obesity and overweightObesity and overweight
Physical inactivityPhysical inactivity
Cigarette smokingCigarette smoking
Excess alcohol intakeExcess alcohol intake
High carbohydrate diets (>60% of energy intake)High carbohydrate diets (>60% of energy intake)
Several diseases (type 2 diabetes, chronic renal failure, nephroticSeveral diseases (type 2 diabetes, chronic renal failure, nephrotic
syndrome)syndrome)
Certain drugs (corticosteroids, estrogens, retinoids, higher doses ofCertain drugs (corticosteroids, estrogens, retinoids, higher doses of
beta-blockers)beta-blockers)
Various genetic dyslipidemiasVarious genetic dyslipidemias
26. Hypertriglyceridemia Increases CHD Risk inHypertriglyceridemia Increases CHD Risk in
Patients with Low HDL-C LevelsPatients with Low HDL-C Levels
* Bar represents 5% of subjects in which 25% of CHD events occurred. Assmann G, Schulte H. Am J Cardiol 1992;70:733–737.
24 31
116
245
0
50
100
150
200
250
≤ 5.0 > 5.0
*
LDL-C/HDL-C ratio
Incidence
per1,000(in6years)
TG < 200 mg/dL
TG ≥ 200 mg/dL
27. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHD
Copenhagen Male StudyCopenhagen Male Study
4.6%
7.7%
11.5%
0
2
4
6
8
10
12
14
39-97mg/dl (n=982) 98-140 (n=973) >140 (n=951)
Am J Cardiol 1999; 83: 13F-16F
Triglyceride level
(mg/dL)
CumulativeincidenceofCHD
andall-causemortality
N=2906; 8years
28. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHD
Cumulative Incidence of MI
Cumulative Incidence of IHD
29. Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHD
Cumulative Incidence of Total Death
30. <130
LDL-C
300
250
200
150
100
50
0
18
43
38
47
56
112 107
255
Elevated triglycerides: A synergistic risk factorElevated triglycerides: A synergistic risk factor
TG < 200 mg/dl
TG > 200 mg/dl
130-159 160-189 >190
CHDcases/1000in8years
PROCAM Study: Incidence of coronary heart disease events according to serum LDL-C and triglyceride concentration
40. Schematic SummarySchematic Summary
The suppression of lipoprotein lipase and
very-low-density lipoprotein (VLDL)
production by insulin is defective in
insulin resistance, leading to increased
free fatty acid (FFA) flux to the liver and
increased VLDL production, which
results in increased circulating
triglyceride concentrations. The
triglycerides are transferred to low-
density lipoprotein (LDL) and high-
density lipoprotein (HDL), and the
VLDL particle gains cholesterol esters by
the action of the cholesterol ester transfer
protein (CETP). This leads to increased
catabolism of HDL particles by the liver
and loss of apolipoprotein (Apo) A,
resulting in low HDL concentrations.
The triglyceride-rich LDL particle is
stripped of the triglycerides, resulting in
the accumulation of atherogenic small,
dense LDL particles.
42. Increased susceptibility to oxidation
Increased vascular permeability
Conformational change in apo B
Decreased affinity for LDL receptor
Association with insulin resistance syndrome
Association with high TG and low HDL
Small Dense LDL and CHD:Small Dense LDL and CHD:
Potential Atherogenic MechanismsPotential Atherogenic Mechanisms
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
43. Accumulation of chylomicron remnants
Accumulation of VLDL remnants
Generation of small, dense LDL-C
Association with low HDL-C
Increased coagulability
- plasminogen activator inhibitor (PAI-1)
- factor VIIc
- Activation of prothrombin to thrombin
Hypertriglyceridemia and CHD Risk:Hypertriglyceridemia and CHD Risk:
Associated AbnormalitiesAssociated Abnormalities
44. ATP III Lipid and Lipoprotein ClassificationATP III Lipid and Lipoprotein Classification
LDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl)LDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl)
<100<100 OptimalOptimal < 40 Low< 40 Low
100-129 Near/Above Optimal100-129 Near/Above Optimal >> 60 High60 High
(Desirable)(Desirable)
130-159 Borderline High130-159 Borderline High
160-189 High160-189 High
>>190190 Very HighVery High
Categories of Risk that Modify LDL GoalsCategories of Risk that Modify LDL Goals
CHD and CHD risk equivalentsCHD and CHD risk equivalents <100<100
Multiple (2+) risk factorsMultiple (2+) risk factors <130<130
Zero to one risk factorZero to one risk factor <160<160
45. Treating Elevated TriglyceridesTreating Elevated Triglycerides
Non-HDL Cholesterol: Secondary TargetNon-HDL Cholesterol: Secondary Target
Primary target of therapy: LDL cholesterolPrimary target of therapy: LDL cholesterol
Achieve LDL goal before treating non-HDL cholesterolAchieve LDL goal before treating non-HDL cholesterol
Therapeutic approaches to elevated non-HDL cholesterolTherapeutic approaches to elevated non-HDL cholesterol
– Intensify therapeutic lifestyle changesIntensify therapeutic lifestyle changes
– Intensify LDL-lowering drug therapyIntensify LDL-lowering drug therapy
– Nicotinic acid or fibrate therapy to lower VLDLNicotinic acid or fibrate therapy to lower VLDL
46. Management of dyslipidemiaManagement of dyslipidemia
Primary aim is to achieve LDL goalPrimary aim is to achieve LDL goal
For high TG (200-499 mg/dl), non-HDL is theFor high TG (200-499 mg/dl), non-HDL is the
secondary target of therapysecondary target of therapy
– Increase statin doseIncrease statin dose
OROR
– Add fibrates/nicotinic acidAdd fibrates/nicotinic acid
For HDL < 40 mg/dl drugs such as nicotinic acid orFor HDL < 40 mg/dl drugs such as nicotinic acid or
fibrates have to be consideredfibrates have to be considered
NCEP guidelines, May 2001
47. Managing Very High Triglycerides (≥500 mg/dL)Managing Very High Triglycerides (≥500 mg/dL)
Goal of therapy: prevent acute pancreatitisGoal of therapy: prevent acute pancreatitis
Very low fat diets (Very low fat diets (≤≤15% of caloric intake)15% of caloric intake)
Triglyceride-lowering drug usually required (statins, fibrate orTriglyceride-lowering drug usually required (statins, fibrate or
nicotinic acid)nicotinic acid)
Reduce triglyceridesReduce triglycerides beforebefore LDL loweringLDL lowering
48. First-line agentsFirst-line agents
HMG CoA reductase inhibitorHMG CoA reductase inhibitor
Fibric acid derivativeFibric acid derivative
Second-line agentsSecond-line agents
Bile acid binding resinsBile acid binding resins
Nicotinic acidNicotinic acid
Pharmacologic Agents for Treatment ofPharmacologic Agents for Treatment of
DyslipidemiaDyslipidemia
American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.
In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.
Effect on lipoprotein
LDL HDL Triglyceride
49. LDL cholesterol lowering*LDL cholesterol lowering*
First choice: HMG CoA reductase inhibitor (statin)
Second choice: Bile acid binding resin or fenofibrate
HDL cholesterol raisingHDL cholesterol raising
Behavior interventions such as weight loss, increased physical
activity and smoking cessation
Glycemic control
Difficult except with nicotinic acid, which is relatively
contraindicated or fibrates
Triglyceride loweringTriglyceride lowering
Glycemic control first priority
Fibric acid derivative (gemfibrozil, fenofibrate)
Statins are moderately effective at high dose in
hypertriglyceridemic subjects who also have high LDL cholesterol
* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as
efficacy of the available agents.
Order of Priorities for Treatment of DiabeticOrder of Priorities for Treatment of Diabetic
Dyslipidemia in Adults*Dyslipidemia in Adults*
51. Statins: Mechanism of ActionStatins: Mechanism of Action
LDL receptor–mediated hepatic uptakeLDL receptor–mediated hepatic uptake
of LDL and VLDL remnantsof LDL and VLDL remnants
Serum VLDL remnantsSerum VLDL remnants
Serum LDL-CSerum LDL-C
CholesterolCholesterol
synthesissynthesis
LDL receptorLDL receptor
(B–E receptor)(B–E receptor)
synthesissynthesis
Intracellular CholesterolIntracellular Cholesterol
Apo BApo B
Apo EApo E
Apo BApo B
Systemic CirculationSystemic CirculationHepatocyteHepatocyte
Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor andReduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and
increases the uptake of non-HDL particles from the systemic circulation.increases the uptake of non-HDL particles from the systemic circulation.
LDLLDL
Serum IDLSerum IDL
VLDLVLDLRR
VLDLVLDLRR
VLDLVLDL
53. Rosuvastatin: The Switch Over AdvantageRosuvastatin: The Switch Over Advantage
0
10
20
30
40
Percentage
reduction
Lipid Parameters
Rosuvastatin Naïve 39.9 28.8 9.2
Switch Over to
Rosuvastatin
24.5 16.6 3.8
LDL-C TC TG
Reduction in LDL-C, TC and
TG in both rosuvastatin
naïve and switch over
patients.
Improvement in LDL-C
targets from 29% to 72.9% in
switch over group.
54. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of Action
Interaction of FibratesInteraction of Fibrates
with PPARwith PPAR αα
55. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of Action
Fibrates lower small dense LDLFibrates lower small dense LDL
56. Fibric Acid derivates: Mechanism of ActionFibric Acid derivates: Mechanism of Action
PPARPPAR αα activated by fibrates negativelyactivated by fibrates negatively
regulates fibrinogen- β expressionregulates fibrinogen- β expression
57. Nicotinic Acid: Mechanism of ActionNicotinic Acid: Mechanism of Action
LiverLiver CirculationCirculation
HDLHDL
Serum VLDL results inSerum VLDL results in
reduced lipolysis to LDLreduced lipolysis to LDL
Serum LDLSerum LDL
VLDL
Decreases hepatic production of VLDL and of apo BDecreases hepatic production of VLDL and of apo B
VLDL secretionVLDL secretion
Apo BApo B
HepatocyteHepatocyte Systemic CirculationSystemic Circulation
Mobilization of FFAMobilization of FFA
TG synthesisTG synthesis
VLDL
LDL
58. Acyl-CoA
synthase
FA Uptake
FA
Glycerol-3-P Lyso PA PA
DAG
DGAT
TG
Phospholipids
Acyl-CoA Acetyl CoA
Glucose
Uptake
Lipogenesis
Acetyl-CoA
carboxylase
FA synthase
VLDL
Apo B-100
NEFA
Hormone-Sensitive Lipase
Adipose TG
Degradation
PAP
Cell membrane
Triglyceride-Lowering Mechanisms of Omega-3 FATriglyceride-Lowering Mechanisms of Omega-3 FA
Mitochondria
CPT-I, -II
Acyl-CoA
dehydrogenase
Peroxisome
Acyl-CoA oxidase
(rodents only?)
+
+
+
+
Β-oxidation
–
–
–
––
В-oxidation
Harris WS and Bulchandani D. Curr Opin Lipidol 2006; 17:387-393.
Lipoprotein classes and inflammation All the major lipoprotein classes impact in some way on the inflammatory process that leads to development of atherosclerosis. The triglyceride-rich lipoproteins—chylomicrons, very low density lipoprotein (VLDL), and their catabolic remnants—and low-density lipoprotein (LDL) are potentially proinflammatory, whereas high-density lipoprotein (HDL) is potentially anti-inflammatory. References: Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:670-676. Colome C, Martinez‑Gonzalez J, Vidal F, de Castellarnau C, Badimon L. Small oxidative changes in atherogenic LDL concentrations irreversibly regulate adhesiveness of human endothelial cells: effect of the lazaroid U74500A. Atherosclerosis 2000;149:295-302. Cockerill GW, Rye K-A, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
Atherogenic particles Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins —very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)— may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles.
Structure of LDL Of all of the plasma lipoproteins, LDL has been most investigated in terms of its role in inflammation. LDL consists of a surface monolayer of phospholipids and free cholesterol and a single molecule of apolipoprotein (apo) B, which encircles the lipoprotein. This surface monolayer surrounds a hydrophobic core of mainly cholesteryl esters but also some triglycerides. In itself, LDL is almost certainly not proinflammatory, but the particle can become modified in many ways. It is the modified LDL particle that is proinflammatory and proatherogenic. Reference: Murphy HC, Burns SP, White JJ, Bell JD, Iles RA. Investigation of human low-density lipoprotein by 1 H nuclear magnetic resonance spectroscopy: mobility of phosphatidylcholine and sphingomyelin headgroups characterizes the surface layer. Biochemistry 2000;39:9763-9770. Structure of HDL HDL has the same essential structure as LDL, with a surface monolayer of phospholipids and free cholesterol and a hydrophobic core consisting mainly of cholesteryl esters but also some triglyceride. However, HDL particles are smaller and contain different apolipoproteins, mainly apo A-I and apo A-II. Both these apolipoproteins have properties that protect the lipids against oxidative modification. In addition, some of the other proteins transported by HDL, such as paraoxonase, have antioxidant properties. Therefore, whereas LDL is very susceptible to oxidative modification, HDL is relatively resistant to it, and this is one of the reasons underlying the anti-inflammatory properties of HDL. Reference: Rye KA, Clay MA, Barter PJ. Remodelling of high density lipoproteins by plasma factors. Atherosclerosis 1999;145:227-238.
Fat in the diet consists of cholesterol as well as triglycerides. Dietary cholesterol is incorporated into micelles together with the biliary cholesterol that was already present. Dietary triglycerides are partially broken down by pancreatic lipases into fatty acids and monoglycerides, which are also incorporated into micellar particles.
Peripheral tissues produce within cells all the cholesterol needed for cellular homeostasis. However, the liver is the only organ that is capable of degrading cholesterol. Therefore, cholesterol must be transported through blood to the liver for processing, degradation, and secretion into bile. Because cholesterol is an insoluble molecule, it must be packaged and transported by special particles in the plasma called lipoproteins. High-density lipoproteins (HDL) are responsible for movement of most cholesterol from peripheral tissues through the blood back to the liver. Because the liver is the center of cholesterol homeostasis in the body, cholesterol that moves from peripheral tissues to the liver is considered to be moving in the reverse direction.
Molecular and histologic pathways for reverse cholesterol transport. To deliver peripheral cholesterol back to the liver or steroidogenic organs such as the adrenal glands, placenta, or ovaries, apoA-I and nascent discoidal HDL interact with cells such as macrophages and foam cells within blood vessel walls. The HDL undergoes a series of cell receptor–dependent and serum enzyme–dependent maturation and speciation reactions (HDL speciation). HDL can interact directly with a variety of hepatocyte surface receptors, including SR-BI. The cholesterol esters in HDL can also be transported back to the liver by an indirect pathway for reverse cholesterol transport that depends on CETP and the LDL and LDL-RRP receptors. ABCA1, ATP-binding membrane cassette transporter A1; apoA-I, apoprotein A-I; ApoE, apoprotein E; CE, cholesteryl ester; CETP, cholesterol ester transfer protein; GI, gastrointestinal; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LDL-RRP, low-density lipoprotein receptor–related protein; Lyso PC, lysophosphatidylcholine; PC, phosphatidylcholine; PGN, proteoglycan; PL, phospholipid; PLTP, phospholipid transfer protein; SR-BI, scavenger receptor BI; UC, unesterified cholesterol; VLDL, very low-density lipoprotein. (Reproduced with permission from Toth PP: High-density lipoprotein as a therapeutic target: Clinical evidence and treatment strategies. Am J Cardiol 96:50K-58K, 2005.)
Cellular cholesterol homeostasis in various tissues. A, Cholesterol homeostasis (hepatocytes). B, Cellular cholesterol efflux (peripheral cells). C, Selective uptake of cholesterol (adrenal cells, hepatocytes, endothelial cells). D, Adipocytes and E, macrophages foam cells. ABCA1 = ATP-binding cassette transporter A1; ABCG1 = ATP-binding cassette transporter G1; ACAT = acyl-coenzyme A:cholesterol acyltransferase; Apo = apolipoprotein; ASP = acylation-stimulating protein; CE = cholesterol esters; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; HMG CoA Red = hydroxymethylglutaryl coenzyme A reductase; HSL = hormone-sensitive lipase; IDL = intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; LDL = low-density lipoprotein; LDL-R = low-density lipoprotein receptor; LRP = low-density lipoprotein receptor–related peptide; PLTP = phospholipid transfer protein; sER = smooth endoplasmic reticulum; SR-B1 = scavenger receptor B1; TG = triglycerides; VLDL = very-low-density lipoprotein; VLDL-R = very-low-density lipoprotein receptor.
The liver is a unique organ because it is capable of cholesterol catabolism and conversion of cholesterol into bile salts. The liver expresses an enzyme called cholesterol-7 -hydroxylase, which is the first and rate-limiting step of a complex enzymatic cascade in which the steroid nucleus of cholesterol is hydroxylated in two or three positions and the side chain of cholesterol is shortened and carboxylated. The end product is a molecule called a bile salt. One of the two bile salts produced in the livers of humans is called cholate, as shown on this slide. Although similar in appearance to cholesterol, cholate is quite a different molecule in its physical properties. Unlike cholesterol, which is highly insoluble in water, bile salts are highly soluble detergent-like molecules. Detergents are molecules that can aggregate to transport otherwise insoluble molecules, such as cholesterol, in an aqueous environment.
There are three main points of regulation for cholesterol absorption into the body. When the micellar particle comes in the proximity of an enterocyte, cholesterol is transported into the enterocyte through a channel recently identified as NPC1L1. A fraction of this cholesterol is pumped back out of the enterocyte into the intestinal lumen by the complex ABCG5/G8, and the remainder is esterified by the enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) into cholesteryl esters. Reference: Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-1204.
Triglycerides are assimilated into the body by the separate absorption of fatty acids and monoglycerides, which are re-esterified by the enzyme acyl-coenzyme A:diglycerol acyltransferase (DGAT) to form triglycerides.
Triglycerides and cholesteryl esters are incorporated, together with apolipoprotein (apo) B-48, to form chylomicron particles, which are exocytosed into the lymph and then enter the circulation.
Intestinal cholesterol absorption Intestinal cholesterol absorption is an important origin of circulating LDL-C. Although dietary cholesterol does contribute, the majority (2/3 to 3/4) of cholesterol delivered to the intestine is derived from biliary cholesterol excretion. Intestinal cholesterol undergoes micellar adaptation by bile acids and is then absorbed into the intestinal cells. The ensuing free cholesterol may subsequently be "pumped" back into the intestine through adenosine triphosphate – binding cassette (ABC) transporters ABCG5 and ABCG8. Alternatively, intestinal free cholesterol may be esterified through acyl-coenzyme A:cholesterol acyltransferase (ACAT), and then packaged into chylomicrons (CMs) in the intestinal epithelial cell by microsomal triglyceride transfer protein (MTP). As CMs leave the intestine, their cholesterol is transported through the lymphatic system to the liver. Reference: Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
HDL is assembled through the combination of cholesterol, phospholipids, and apo A I, produced in the liver and gut. Cholesterol is incorporated in part by the action of the adenosine triphosphate-binding cassette-1 and is then esterified by lecithin CE transfer protein (LCAT) allowing HDL to enlarge into spherical HDL3 and HDL2. VLDL is secreted by the liver and processed on the vascular endothelium by LPL. LPL is activated by apo C II and inhibited by apo C III. CMs are secreted by the gut. Phospholipids released by lipolysis of both CM and VLDL contribute to the formation of small dense pre |[beta]| or discoidal HDL and the VLDL remnant particle is either taken up directly by the liver through the lipoprotein-like receptor or is transformed into LDL by action of CE transfer protein, exchanging the CE-rich core of HDL with VLDL TGs. CM remnants are taken up by the liver. TG-rich HDL is then processed by HL into smaller dense HDL. Mature HDL2 either transfers CEs to the liver by interaction with the scavenger receptor B-1 or transfers its CE-rich core to VLDL remnants creating LDL. Small dense pre |[beta]| or discoidal HDL is subject to accelerated degradation in part by the kidney.
The exogenous, endogenous, and reverse cholesterol pathways. The exogenous pathway transports dietary fat from the small intestine as chylomicrons to the periphery and the liver. The endogenous pathway denotes the secretion of very low density lipoprotein (VLDL) from the liver and its catabolism to intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL). Triglycerides are hydrolyzed from the VLDL particle by the action of lipoprotein lipase (LPL) in the vascular bed, yielding free fatty acids (FFAs) for utilization and storage in muscle and adipose tissue. High-density lipoprotein (HDL) metabolism is responsible for the transport of excess cholesterol from the peripheral tissues back to the liver for excretion in the bile. Nascent HDL-3 particles derived from the liver and small intestine are esterified to more mature HDL-2 particles by enzyme-mediated movement of chylomicron and VLDL into the HDL core, which is removed from the circulation by endocytosis.
Endogenous lipid metabolism. In the liver, triglycerides (TGs), cholesteryl esters (CEs), and apolipoprotein B100 are packaged as very low density lipoprotein (VLDL) particles. TG is hydrolyzed by lipoprotein lipase (LPL) to generate intermediate density lipoprotein (IDL), which is further metabolized to generate low density lipoprotein (LDL). This particle can be removed by the liver or by peripheral cells. Cholesterol derived from LDL regulates several processes and can be used for the synthesis of bile acids, steroid hormones, and cell membranes.
Pathways involved in chylomicron remnant metabolism. In sequestration, chylomicron remnants are trapped in the space of Disse, through proteoglycan binding mediated by apolipoprotein E (E). In processing, enzymes, including lipases, can continue processing the remnants to smaller particles. In uptake, receptors involved in the uptake of the remnants appear to include the low-density lipoprotein (LDL) receptor and the LDL receptor–related protein (LRP). Apo-E, apolipoprotein E; HL, hepatic lipase; HSPG, heparan sulfate proteoglycans; LPL, lipoprotein lipase.
Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels Prospective Cardiovascular Münster Study In the Prospective Cardiovascular Münster Study (PROCAM), 1 triglyceride levels 200 mg/dL doubled the coronary heart disease (CHD) risk in patients with elevated ratios (> 5.0) of low- to high-density lipoprotein cholesterol (LDL-C/HDL-C). Most patients with LDL-C/HDL-C values > 5.0 had HDL-C levels < 39 mg/dL. These data suggest that hypertriglyceridemic patients with reduced HDL-C levels are at particularly high risk of CHD. Reference: Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Münster study. Am J Cardiol. 1992;70:733–737.
Evidence from the 8-year Copenhagen Male Study involving 2906 men further substantiated that triglyceride levels were independently related to increased CHD risk. The relation between triglycerides and CHD risk was inspite of adjusting for HDL.
In a prospective cohort study of 7587 women and 6394 men, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004, the cumulative incidence of myocardial infarction, ischemic heart disease and total death increased with increasing levels of non-fasting triglycerides. Nordestgaard BG, Benn M, Schnohr P, et al . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease and death in men and women. JAMA . 2007;298(3):299-308
In a prospective cohort study of 7587 women and 6394 men, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004, the cumulative incidence of myocardial infarction, ischemic heart disease and total death increased with increasing levels of non-fasting triglycerides. Nordestgaard BG, Benn M, Schnohr P, et al . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease and death in men and women. JAMA . 2007;298(3):299-308
Importantly, triglycerides are not just an independent risk factor for CHD, they also exhibit a synergistic relationship in terms of increased CHD risk, as shown by the PROCAM study. As seen in this slide, at any level of LDL, an elevated level of triglycerides further increases the risk of CHD. Eur Heart J 1998; 19 (Suppl M): M8-M14.
We have understood for decades the roles of ‘classical’ risk factors – elevated LDL-cholesterol, hypertension, elevated blood glucose and smoking – in the pathogenesis of cardiovascular disease. More recent research is continuing to define the contribution of emerging risk factors to the risk of developing type 2 diabetes and cardiovascular disease, particularly in the setting of insulin resistance. Abdominal obesity is associated with multiple cardiometabolic risk factors such as atherogenic elevated blood glucose (hypertriglyceridaemia and low HDL-cholesterol), elevated blood glucose and inflammation, which are major drivers of cardiovascular disease and type 2 diabetes. In addition, atherosclerosis is increasingly regarded as an inflammatory condition.
In addition to type 2 diabetes, insulin resistance is a pathogenic factor in the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidaemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricaemia, polycystic ovary disease, and obesity. American Diabetes Association. Consensus Development Conference on Insulin Resistance, 5–6 November 1997. Diabetes Care 1998;21(2):310–314.
Ethnic Variations in Lipid Parameters Insulin Resistance Atherosclerosis Study Small, dense low-density lipoprotein (LDL) particle size is now recognized as a risk factor for cardiovascular disease (CVD). LDL size was investigated as a possible explanation for differences in CVD rates among African-Americans, Hispanics, and non-Hispanic whites in the Insulin Resistance Atherosclerosis Study (IRAS). As this slide shows, LDL size differed significantly ( P < 0.001) by ethnic group, as did high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. A comparison of the three ethnic groups revealed that reduced LDL size was associated with lower HDL-C levels and higher TG levels. African-Americans had higher HDL-C and lower TG levels than non-Hispanic whites. Hispanics had the opposite pattern, with lower HDL-C and higher TG levels than non-Hispanic whites. Reference: Haffner SM, D’Agostino R Jr, Goff D, et al. LDL size in African Americans, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Arterioscler Thromb Vasc Biol. 1999;19:2234–2240.
Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study In a nested case-control study within the Quebec Cardiovascular Study, the relationship between fasting insulin, which is a surrogate marker for insulin resistance, and CHD was examined in men who were principally nondiabetic. Subjects were stratified by low (<12 µU/ml), medium (12-15 µU/ml), and high (>15 µU/ml) insulin levels and by low (<150 mg/dL) and high (>150 mg/dL) triglycerides. The study found that high insulin levels predicted CHD both in men with low triglycerides and in men with high triglycerides. However, triglyceride level was not a significant predictor of CHD once one adjusted for insulin level. These results bring up an interesting but difficult area in cardiovascular epidemiology, which is whether triglyceride is a risk factor for CHD. Approximately 20 years ago, Stephen Hulley et al. suggested that triglyceride level was not a risk factor for CHD once adjustment was made for HDL. Although Hulley has been criticized for this view, few analyses that have looked at the possible relation between triglyceride and CHD have adjusted for whether people were diabetic. Because of the relation of triglyceride level to insulin level and possibly glucose level, most of the relation between triglyceride and CHD in observational studies may be due to confounding. To evaluate fully the effects of lowering triglyceride level on CHD, one has to look at clinical trial data as opposed to observational data. Among interventional studies, confounding may be less important in trials of behavioral interventions to lower triglyceride, because weight loss and increased physical activity not only lower triglyceride level but also improve insulin sensitivity and lower blood pressure. In contrast, if triglyceride is lowered by pharmacological means such as with a fibrate or a high-dose statin, there will be little effect on blood pressure or insulin sensitivity. References: Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957. Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease. N Engl J Med 1980;302:1383-1389.
Mechanisms Relating Insulin Resistance and Dyslipidemia (I) The pathophysiologic basis for diabetic dyslipidemia and its relation to insulin resistance is presented over the next four slides. In the first, we see that insulin-resistant fat cells undergo greater breakdown of their stored triglycerides and greater release of free fatty acids into the circulation. This is a common abnormality seen in both obese and nonobese insulin-resistant subjects and those with type 2 diabetes. Increased fatty acids in the plasma leads to increased fatty acid uptake by the liver; in the fed state and in the presence of adequate glycogen stores, which is the common situation in patients with type 2 diabetes that is reasonably well controlled and certainly the case in the insulin-resistant nondiabetic subject, the liver takes those fatty acids and synthesizes them into triglycerides.
Mechanisms Relating Insulin Resistance and Dyslipidemia (II) The presence of increased triglycerides stimulates the assembly and secretion of the apolipoprotein (apo) B and very low density lipoprotein. The result is an increased number of VLDL particles and increased level of triglycerides in the plasma, which leads to the rest of the diabetic dyslipidemic picture.
Mechanisms Relating Insulin Resistance and Dyslipidemia (III) In the presence of increased VLDL in the plasma and normal levels of activity of the plasma protein cholesteryl ester transfer protein (CETP), VLDL triglycerides can be exchanged for HDL cholesterol. That is, a VLDL particle will give up a molecule of triglyceride, donating it to the HDL, in return for one of the cholesteryl ester molecules from HDL. This leads to two outcomes: a cholesterol-rich VLDL remnant particle that is atherogenic, and a triglyceride-rich cholesterol-depleted HDL particle. The triglyceride-rich HDL particle can undergo further modification including hydrolysis of its tryglyceride, probably by hepatic lipase, which leads to the dissociation of the structurally important protein apo A-I. The free apo A-I in plasma is cleared more rapidly than apo A-I associated with HDL particles. One of the sites of clearance is the kidney. In this situation, HDL cholesterol is reduced, and the amount of circulating apo A-I and therefore the number of HDL particles is also reduced.
Mechanisms Relating Insulin Resistance and Dyslipidemia (IV) On the last slide in this series, we see a similar phenomena leading to small, dense LDL. Increased levels of VLDL triglyceride in the presence of CETP can promote the transfer of triglyceride into LDL in exchange for LDL cholesteryl ester. The triglyceride-rich LDL can undergo hydrolysis by hepatic lipase or lipoprotein lipase, which leads to a small, dense, cholesterol-depleted—and, in general, lipid-depleted—LDL particle.
Schematic summary relating insulin resistance (IR) to the characteristic dyslipidemia of type 2 diabetes mellitus. IR at the adipocyte results in increased free fatty acid (FFA) release. Increased FFA flux stimulates very-low-density lipoprotein (VLDL) secretion, causing hypertriglyceridemia (TG). VLDL stimulates a reciprocal exchange of TG to cholesteryl ester (CE) from both high-density lipoprotein (HDL) and low-density lipoprotein (LDL), catalyzed by CE transfer protein (CETP). TG-enriched HDL dissociates from ApoA-1, leaving less HDL for reverse cholesterol transport. TG-enriched LDL serves as a substrate for lipases that convert it to atherogenic small, dense LDL particles (SD LDL). (From Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest 2000;106:453-458.)
Insulin resistance and dyslipidemia. The suppression of lipoprotein lipase and very-low-density lipoprotein (VLDL) production by insulin is defective in insulin resistance, leading to increased free fatty acid (FFA) flux to the liver and increased VLDL production, which results in increased circulating triglyceride concentrations. The triglycerides are transferred to low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and the VLDL particle gains cholesterol esters by the action of the cholesterol ester transfer protein (CETP). This leads to increased catabolism of HDL particles by the liver and loss of apolipoprotein (Apo) A, resulting in low HDL concentrations. The triglyceride-rich LDL particle is stripped of the triglycerides, resulting in the accumulation of atherogenic small, dense LDL particles.
Dyslipidemia in Diabetes As described in the preceding slides, high triglyceride and high VLDL levels lead to low HDL, fewer HDL particles, and small, dense LDL.
Small, Dense LDL and CHD: Potential Atherogenic Mechanisms Data from in vitro and in vivo studies suggest that small, dense LDL may be particularly atherogenic. In vitro, small, dense LDL appears to be more susceptible to oxidative modification. Because they are smaller, these particles appear to penetrate the endothelial layer of the arterial wall more easily. The apo B molecule in small, dense LDL undergoes a conformational change that leads to decreased affinity for the LDL receptor, therefore allowing this LDL particle to remain in the circulation longer and be more liable to oxidative modification and uptake into the vessel wall. Finally, in population studies and small clinical studies, small, dense LDL is associated with the insulin-resistance syndrome as well as with high triglycerides and low HDL cholesterol. Reference: Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-171.
Hypertriglyceridemia and CHD Risk: Associated Abnormalities One should not focus extensively on the atherogenic potential of small, dense LDL to the exclusion of considering hypertriglyceridemia as a risk factor. There are a number of reasons to consider hypertriglyceridemia as at least a marker of increased atherogenic potential. First of all, hypertriglyceridemia is associated with the accumulation of chylomicron remnants, which we know can be atherogenic, and accumulation of VLDL remnants, which are also atherogenic. As previously discussed, hypertriglyceridemia generates small, dense LDL and is the basis for low HDL in the general population. Hypertriglyceridemia is also associated with increased coagulability and decreased fibrinolysis, as shown by its association with increased levels of plasminogen activator inhibitor 1 (PAI-1) and factor VII and its activation of prothrombin to thrombin.
Pharmacologic Agents for Treatment of Dyslipidemia In this slide, we can see a summary of the actions of the different classes of drugs available for treating the dyslipidemia of diabetes. The HMG-CoA reductase inhibitors, or statins, are very effective in lowering LDL cholesterol levels in patients with diabetes, have variable but often significant effects on triglyceride levels, and have a modest but potentially important ability to raise HDL cholesterol levels. The fibrates, of which gemfibrozil and fenofibrate are available in the United States, are very good at lowering triglycerides and raising HDL cholesterol levels. These effects of fibrates on triglycerides are usually better than those seen with statins. On the other hand, fibrates often have little effect on LDL cholesterol, and can even result in increased LDL levels in patients with more severe hypertriglyceridemia. Fenofibrate can lower LDL cholesterol significantly when used in patients with very high baseline LDL cholesterol levels. The bile acid–binding resins can achieve additional LDL cholesterol lowering when used with a statin, although GI side effects of the older resins may be particularly problematic in patients with diabetes. Newer, more potent bile acid sequestrants, such as colesevalem, may increase their efficacy in the diabetic population. Niacin is the best agent for raising HDL cholesterol and has significant effects on triglycerides and a modest ability to lower LDL cholesterol. Niacin appears to increase insulin resistance, however, and its use may require modification of the diabetic treatment regimen. Reference: American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults This slide presents the priorities for treating abnormalities of lipid metabolism set by the American Diabetes Association. LDL lowering is the first priority, based on the clinical trials showing marked reductions in morbidity when statins lower LDL cholesterol in the subgroups with diabetes. Raising HDL cholesterol is the second priority, followed by lowering triglycerides. ADA goals for all diabetics include an LDL cholesterol less than or equal to 100 mg/dL, an HDL cholesterol greater than 45 mg/dl (possibly even higher in women), and a triglyceride level less than 200 mg/dL. Reference: American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60.
The molecular mechanisms by which statins act include inhibiting the rate of conversion of acetate molecules into cholesterol by the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in cholesterol biosynthesis. Because a precise amount of cholesterol is required in cells, inhibition of synthesis leads to a homeostatic response in which cells increase the density of LDL receptors on their surface. This increases the clearance rate of LDL particles from the plasma and reduces plasma LDL cholesterol secondarily.
Statins: mechanism of action As inhibitors of hepatic HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in hepatic cholesterol synthesis, statins decrease synthesis of cholesterol by the liver, which results in two important effects: the up-regulation of LDL receptors by hepatocytes and consequent increased removal of apolipoprotein (apo) E – and B – containing lipoproteins from the circulation, and a reduction in the synthesis and secretion of lipoproteins from the liver. The net effect of statin therapy is to lower plasma concentrations of cholesterol-carrying lipoproteins, the most prominent of which is LDL. Importantly, however, statins also increase the removal and reduce the secretion of remnant particles, i.e., very low density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). This means that in patients who have an elevation of both LDL-C and triglycerides (indicating increased levels of triglyceride-rich VLDL and IDL remnants as well as LDL), a statin is one of the therapies of choice because of its ability to effectively lower LDL-C and non – high-density lipoprotein cholesterol (non-HDL-C) levels.
Statins reduce TG levels in the range of 10% to 20%. Higher the baseline TG level, the greater the TG-lowering effect. AFCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT: Anglo Scandinavian Cardiac Outcome Trial; CARDS: Collaborative AtoRvastatin Diabetes Study; CARE: Cholesterol and Recurrent Events Study; HPS: Heart Protection Study; JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LIPID: Long-Term Intervention with Pravastatin in Ischemic Disease; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk; TG: triglyceride; 4s: Scandinavian Simvastatin Survival Study; WOSCOPS: West of Scotland Coronary Prevention Study. What Are the Effects of Statins on Triglycerides and What Are the Results of Major Outcomes Studies? Downloaded from http://cme.medscape.com
Rosuvastatin significantly decreased the levels of Low density cholesterol, Total cholesterol and triglycerides in both rosuvastatin naïve patients and patients switched over to rosuvastatin. In patients switched to rosuvastatin, achievement of target LDL-C levels improved from 29% to 72.9%. Tan AT , Low LP , Lim CH , et al . Effects of rosuvastatin on low-density lipoprotein cholesterol and plasma lipids in Asian patients with hypercholesterolemia. J Atheroscler Thromb . 2009;16(4):509-16.
The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
The primary mode of action of the fibrates is via activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolize fatty acids, such as the liver, kidney, heart and muscle. On activation, PPARα binds as heterodimers with RXR, which subsequently recognises and binds to specific PPARα response elements leading to modulation of expression of the target genes. The result is an increase in apo A-1, lipoprotein lipase and HDL levels and decrease in apo CIII, which promotes the clearance of circulating triglyceride-rich lipoproteins. In addition, fibrates promote a shift in the density of LDL particles towards larger, more buoyant particles that are less susceptible to oxidation and have increased affinity for the LDL receptor. Fibrates also exert pleiotropic effects in the artery wall. PPARα is involved in the control of the anti-inflammatory response, via inhibition of the transcription factor NFκB. Fibrates can also attenuate the production of pro-inflammatory stimuli such as interleukin 6 (IL-6) and various prostaglandins, as well as the acute phase proteins, including fibrinogen and C-reactive protein. Fibrates: Therapeutic Review: Mechanism of Action of Fibrates. Available from: http://www.medscape.com.
Nicotinic acid: mechanism of action The last of our LDL-C – lowering drugs is nicotinic acid, or niacin. Niacin appears to exert its effects by inhibiting lipoprotein synthesis and decreasing the production of VLDL particles by the liver. It inhibits the peripheral mobilization of free fatty acids, thus reducing hepatic synthesis of triglycerides and the secretion of VLDL. It also reduces apo B. The net result is a reduction in VLDL particles secreted by the liver and thus less substrate to make LDL particles. It increases the production of apo A-I and thereby HDL through mechanisms that are not clear.
Potential triglyceride-lowering mechanisms of omega-3 FA Feeding omega-3 FA has been shown to inhibit (–) lipogenesis and the activities of diacylglycerol acyltransferase (DGAT), phosphatidic acid (PA), and hormone-sensitive lipase and to stimulate (+) β-oxidation, phospholipid synthesis, and apo B degradation. The end result is a reduced rate of secretion of very low density lipoprotein (VLDL) triglyceride (TG). Additional abbreviations on slide: FA, fatty acid; CPT, carnitine phosphotransferase; DAG, diacylglycerol; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PAP, phosphatidic acid phosphohydrolase; NEFA, serum nonesterified fatty acids; apo, apolipoprotein. Reference: Harris WS and Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol 2006; 17:387-393.
Dyslipidemia treatment summary. *Exception: Immediate medication (gemfibrozil or niacin) for patients with TG >1000 mg/dL due to high risk of pancreatitis, or LDL-C >220 mg/dL due to genetic disorders and resistance to nonpharmacologic treatment after ruling out secondary causes. †Notes: (1) Goal LDL-C <100 mg/dL (70 mg/dL optional) with CHD/noncoronary atherosclerosis, diabetes mellitus, or 10-yr CHD-risk >20%; (2) Goal LDL-C <130 mg/dL if no known CHD or noncoronary atherosclerosis but high risk; (3) Goal LDL-C >160 mg/dL with ≥2 risk factors or LDL-C >190 mg/dL in isolation. ‡See text: Statins and fibrates and/or niacin may be used in combination with close monitoring for hepatitis or myositis (risk of interaction 2-6%). CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; TG, triglyceride. Modified from McBride PE, Underbakke G, Stein DH: Dyslipidemias. In Taylor RB (ed): Family Medicine: Principles and Practice, 6th ed. New York, Springer-Verlag, 2003, pp 1019-1029.