S-KHALILZADEH. Lipids are hydrophobic molecules that are insoluble in water. They are in cell...
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DIABETES AND LIPID S-KHALILZADEH
S-KHALILZADEH. Lipids are hydrophobic molecules that are insoluble in water. They are in cell membranes as a major form of stored nutrients (triglycerides),
Lipids are hydrophobic molecules that are insoluble in water.
They are in cell membranes as a major form of stored nutrients
(triglycerides), as precursors of adrenal and gonadal steroids and
bile acids as extracellular and intracellular messengers (e.g.,
prostaglandins, phosphatidylinositol). Lipoproteins provide a
vehicle for transporting the complex lipids in the blood as
water-soluble complexes and deliver lipids to cells
Slide 3
Fatty acids vary in length and in the number and position of
double bonds Saturated fatty acids lack double bonds unsaturated
fatty acids have one or more double bonds. Monounsaturated fatty
acids have one double bond, and polyunsaturated fatty acids (PUFAs)
have two or more.
Slide 4
Cholesterol is a four-ring hydrocarbon with an eight-carbon
side chain. It is a major component of cell membranes and as a
precursor of steroid hormones (adrenal and gonadal hormones) and
bile acids In the blood, about two thirds of the cholesterol is
esterified
Slide 5
Slide 6
Triglycerides consist of three fatty acid molecules esterified
to a glycerol molecule Triglycerides store fatty acids and form
large lipid droplets in adipose tissue. They are also transported
as a component of certain lipoproteins. When triglycerides are
hydrolyzed in adipocytes, free fatty acid (FFA) are released to be
used as a source of energy
Slide 7
Slide 8
Chylomicrons are the largest of the plasma lipoproteins
(>1000 in diameter),float after ultracentrifugation of plasma.
They are composed of 98% to 99% lipid (85%-90% triglyceride) and 1%
to 2% protein Chylomicrons are present in postprandial plasma (but
are absent after an overnight fast) and contain apo-B48, apo-AI,
apo-AIV, apo-E, and the C apolipoproteins
Slide 9
VLDLs are particles 300 to 700 They are composed of 85% to 90%
lipid (about 55% triglyceride, 20% cholesterol, and 15%
phospholipid) and 10% to 15% protein. The distinctive
apolipoprotein is apo- B100, the hepatic form of apo-B. VLDLs also
contain apo-E and C apolipoproteins
Slide 10
IDLs present in low concentrations in the plasma and are
intermediate in size and composition between VLDL and LDL Their
proteins are apo-B100 and apo-E. The IDLs are precursors of LDLs
and represent metabolic products of VLDL catabolism in the plasma
by the action of lipases. IDLs are often considered to be VLDL
remnants and to be atherogenic.
Slide 11
LDLs are about 200 in diameter, are the major
cholesterol-carrying lipoproteins in the plasma; about 70% of total
plasma cholesterol is in LDL. LDLs are composed of approximately
75% lipid (about 35% cholesteryl ester, 10% free cholesterol, 10%
triglyceride, and 20% phospholipid) and 25% protein. Apo-B100 is
the principal protein in these particles, with trace amounts of
apo-E
Slide 12
The clearance of LDL is mediated by apo-B100. The affinity of
apo-B100 for the LDL receptor is lower than that of apo-E, and
clearance of LDL is much slower (with a half-life of 2 to 3 days).
Compared with apo-B100 containing LDLs, apo-Econtaining
lipoproteins have 20-fold greater affinity for the LDL
receptor
Slide 13
HDLs are small particles (70-120 in diameter) HDLs contain
about 50% lipid (25% phospholipid, 15% cholesteryl ester, 5% free
cholesterol, and 5% triglyceride) and 50% protein Their major
apolipoproteins are apo-AI (65%), apo-AII (25%), and smaller
amounts of the C apolipoproteins and apo-E
Slide 14
Apo-E is a minor component of a subclass of HDL referred to as
HDL 1, but about 50% of total plasma apo-E is in this HDL fraction.
The major classes of HDLs lack apo-E and do not interact with the
LDL receptor
Slide 15
Apolipoproteins Understanding the major functions of the
different apolipoproteins is important clinically, because defects
in apolipoprotein metabolism lead to abnormalities in lipid
handling
Slide 16
Slide 17
Apolipoproteins A-I Structural protein for HDL; activator of
lecithin-cholesterol acyltransferase (LCAT). A-II Structural
protein for HDL; activator of hepatic lipase. A-IV Activator of
lipoprotein lipase (LPL) and LCAT. B-100 Structural protein for
VLDL, IDL, LDL, and Lp(a); ligand for the LDL receptor; required
for assembly and secretion of VLDL. B-48 Contains 48 percent of
B-100; required for assembly and secretion of chylomicrons; does
not bind to LDL receptor.
Slide 18
C-I Activator of LCAT. C-II Essential cofactor for LPL. C-III
Interferes with apo-E mediated clearance of triglyceride-enriched
lipoproteins by cellular receptors ; inhibits triglyceride
hydrolysis by lipoprotein lipase and hepatic lipase,interferes with
normal endothelial function.
Slide 19
D May be a cofactor for cholesteryl ester transfer protein
(CETP). E Ligand for hepatic chylomicron and VLDL remnant receptor,
leading to clearance of these lipoproteins from the circulation;
ligand for LDL receptor.
Slide 20
Human LPL is synthesized by adipocytes, by myocytes in skeletal
and cardiac muscle, and by macrophages but is not produced by
hepatocytes. LPL is transported to the capillary endothelial cells
where it interacts with chylomicrons and VLDL in the circulation
and mediates the hydrolysis of their triglycerides to FFAs. The
fatty acids are stored as triglyceride in adipocytes and in the
formation of hepatic VLDL.
Slide 21
Hepatic lipase is primarily a phospholipase but also possesses
triglyceride hydrolase activity It is synthesized by hepatocytes
Hepatic lipase is transported from the liver to the capillary
endothelium of the adrenals, ovaries, and testes, where it
functions in the release of lipids from lipoproteins for use in
these organs. Its activity is increased by androgens and reduced by
estrogens
Slide 22
EXOGENOUS PATHWAY OF LIPID METABOLISM starts with the
intestinal absorption of dietary cholesterol and fatty acids The
mechanisms regulating the amount of dietary cholesterol that is
absorbed are unknown. Sitosterolemia is a rare autosomal recessive
disorder associated with hyperabsorption of cholesterol and plant
sterols from the intestine.
Slide 23
Within the intestinal cell, free fatty acids combine with
glycerol to form triglycerides, and cholesterol is esterified by
acyl-coenzyme A:cholesterol acyltransferase (ACAT) to form
cholesterol esters Triglycerides and cholesterol are assembled
intracellularly as chylomicrons. The main apolipoprotein is B-48,
but C-II and E are acquired as the chylomicrons enter the
circulation. Apo B-48 permits lipid binding to the chylomicron but
not to LDL receptor.
Slide 24
Apo C-II is a cofactor for LPL which makes the chylomicrons
smaller by hydrolyzing the core triglycerides and releasing free
fatty acids. The free fatty acids are then used as an energy
source, converted to triglyceride, or stored in adipose tissue. The
end-products of chylomicron are chylomicron remnants that are
cleared from the circulation by hepatic chylomicron remnant
receptors for which apo E is a high-affinity ligand.
Slide 25
Slide 26
ENDOGENOUS PATHWAY OF LIPID METABOLISM begins with the
synthesis of VLDL by the liver Microsomal triglyceride transfer
protein is essential for the transfer of the bulk of triglycerides
into the endoplasmic reticulum for VLDL assembly They include apo
C-II which acts as a cofactor for LPL, apo C-III which inhibits
this enzyme, and apo B-100 and E which serve as ligands for LDL
receptor
Slide 27
The triglyceride core of VLDL particles is hydrolyzed by
lipoprotein lipase. During lipolysis, the core of the VLDL particle
is reduced, generating VLDL remnant particles (also called IDL)
that are depleted of triglycerides via a process similar to the
generation of chylomicron remnants.
Slide 28
Some of the excess surface components in the remnant particle,
including phospholipid, unesterified cholesterol, and
apolipoproteins A, C and E, are transferred to HDL VLDL remnants
can either be cleared from the circulation by the apo B/E (LDL) or
the remnant receptors or remodeled by hepatic lipase to form LDL
particles.
Slide 29
Slide 30
LDL can be internalized by hepatic and nonhepatic tissues.
Hepatic LDL cholesterol can be converted to bile acids and secreted
into the intestinal lumen. LDL cholesterol internalized by
nonhepatic tissues can be used for hormone production, cell
membrane synthesis, or stored in the esterified form
Slide 31
Circulating LDL can also enter macrophages and some other
tissues through the unregulated scavenger receptor. This pathway
can result in excess accumulation of intracellular cholesterol and
the formation of foam cells which contribute to the formation of
atheromatous plaques
Slide 32
These cholesterol-enriched cells can rupture, releasing
oxidized LDL, intracellular enzymes, and oxygen free radicals that
can further damage the vessel wall. Oxidized LDL induces apoptosis
of vascular smooth muscle and human endothelial cells via
activation of a protease which suggests a mechanism for the
response to injury hypothesis of atherosclerosis
Slide 33
Slide 34
anti-atherogenic effect of HDL Apolipoprotein A-I on the
surface of HDL serves as a signal to mobilize cholesterol esters
from intracellular pools. After diffusion of cholesterol onto HDL,
the cholesterol is esterified to cholesterol esters by LCAT, a
plasma enzyme that is activated primarily by apolipoprotein A-I.
HDL can act as an acceptor for cholesterol released during
lipolysis of triglyceride-containing lipoproteins
Slide 35
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Slide 38
Diabetes mellitus insulin deficiency and poor glycemic control
lead to increases in the plasma levels of triglycerides and apo-
Bcontaining lipoproteins insulin deficiency results in impaired LPL
activity and diminished clearance of triglyceride-rich particles.
Insulin deficiency also enhances lipolysis, which increases FFA
flux to the liver, increased FFA flux drives triglyceride and VLDL
synthesis and secretion.
Slide 39
Plasma levels of LDL are increased in some but not all
subjects. the hyperlipidemia in type 2 diabetes is often
characterized by an increase in small, dense LDLs which are
particularly atherogenic a portion of the plasma LDL undergoes
glycosylation, which can increase binding to arterial wall
proteoglycans and susceptibility to oxidation.
Slide 40
(CHD) are common in industrialized societies There is a direct
relation between the plasma levels of total and LDL cholesterol and
the risk of CHD and mortality LDL cholesterol lowering in moderate
to high-risk patients leads to a reduction in cardiovascular events
Abnormalities of plasma lipids (dyslipidemia) other than LDL
cholesterol are common in patients with early onset CHD HDL
cholesterol levels are related to absolute CHD event rates in
treated hypercholesterolemic subjects with and without baseline
clinical CHD Screening tests for dyslipidemia are widely
available
Slide 41
Guidelines developed by the NCEP in 2001 recommend that a
complete plasma lipid profile (total cholesterol, LDL-C, HDL-C, and
triglycerides) be measured in all adults 20 years of age and older
at least once every 5 years
Slide 42
The ATP III recommendations for the treatment of
hypercholesterolemia are based on the LDL-cholesterol (LDL-C)and
are influenced by the coexistence of CHD and the number of cardiac
risk factors. There are five major steps to determining an
individual's risk category, which serves as the basis for the
treatment guidelines
Slide 43
Step 1 The first step in determining patient risk is to obtain
a fasting lipid profile
Slide 44
Step 2 CHD equivalents, that is, risk factors that place the
patient at similar risk for CHD events as a history of CHD itself,
are identified : Diabetes mellitus Symptomatic carotid artery
disease Peripheral arterial disease Abdominal aortic aneurysm
Multiple risk factors that confer a 10-year risk of CHD >20
percent
Slide 45
Step 3 Major CHD factors other than LDL are identified:
Cigarette smoking Hypertension (BP 140/90 or antihypertensive
medication) Low HDL-C (
Slide 46
STEP-4 If two or more risk factors other than LDL (as defined
in step 3) are present in a patient without CHD or a CHD equivalent
(as defined in step 2), the 10-year risk of CHD is assessed using
the ATP III modification of the Framingham risk tables
Slide 47
Step 5 The last step in risk assessment is to determine the
risk category that establishes the LDL goal, when to initiate
therapeutic lifestyle changes, and when to consider drug
therapy
Slide 48
Total-to-HDL-cholesterol ratio Among men, a ratio of 6.4 or
more identified a group at 2 to 14 percent greater risk than
predicted from serum total or LDL-C Among women, a ratio of 5.6 or
more identified a group at 25 to 45 percent greater risk than
predicted from serum total or LDL-C
Slide 49
Non-HDL-cholesterol Non-HDL-C is defined as the difference
between the total cholesterol and HDL-C. Non-HDL-C includes all
cholesterol present in lipoprotein particles that is considered
atherogenic, including LDL,lp(a),IDL and VLDL. It has been
suggested that the non-HDL-C fraction may be a better tool for risk
assessment than LDL-C
Slide 50
ATP III identifies the non-HDL-C concentration as a secondary
target of therapy in people who have high triglycerides 200 mg/dl.
The goal for non-HDL-C in this circumstance is a concentration that
is 30 mg/dL (0.78 mmol/L) higher than that for LDL-C
Slide 51
Slide 52
A standard serum lipid profile consists of total cholesterol,
triglycerides, and HDL- cholesterol. Lipoprotein analysis should be
performed after 9 to 12 hours of fasting to minimize the influence
of postprandial hyperlipidemia. Either a plasma or serum specimen
can be used; the serum cholesterol is approximately 3 percent lower
than the plasma value
Slide 53
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Slide 56
HMG-CoA Reductase Inhibitors Inhibition of cholesterol
biosynthesis up-regulates cellular LDL receptors and enhances
clearance of LDL from the plasma into cells.
Slide 57
Statins Competitive inhibitors of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase, which catalyzes an early,
ratelimiting step in cholesterol biosynthesis
Slide 58
Chemistry The statins possess a side group that is structurally
similar to HMG-CoA Mevastatin, lovastatin, simvastatin, and
pravaslatin are fungal metabolites fluvastatin, atorvastatin, and
rosuvastatin are entirely synthetic Lovastatin and simvastatin are
lactone prodrugs that are modified in the liver to active hydroxy
acid forms Since they are lactones, they are less soluble in water
than are the other statins
Slide 59
Mechanism of Action Statins exert their major effectreduction
of LDL levels- through a mevalonic acid-like moiety that
competitively inhibits HMG-CoA reductase. By reducing the
conversion of HMG-CoA to mevalonate, statins inhibit an early and
rate-limiting step in cholesterol biosynthesis
Slide 60
Slide 61
Inhibition of hepatic cholesterol synthesis, results in
increased expression of the LDL receptor gene Degradation of LDL
receptors also is reduced The greater number of LDL receptors on
the surface of hepatocytes results in increased removal of LDL from
the blood, statins also can reduce LDL levels by enhancing the
removal of LDL precursors (VLDL and IDL) and by decreasing hepatic
VLDL production
Slide 62
Triglyceride Reduction by Statins. Triglyceride levels >250
mgldl are reduced substantially by statins, If baseline
triglyceride levels are below 250 mg/dl. Reductions in
triglycerides do not exceed 25% irrespective of the dose or statin
used simvastatin and atorvastatin, 80,mg/day; rosuvastatin, 40
mg/day experience a 35% to 45% reduction in fasting triglyceride
levels
Slide 63
Effect of Statins on HDL-C Levels patients with elevated LDL-C
levels and gender- appropriate HDL-C levels (40 to 50 mgldl for
men; 50 to 60 mg/dl for women). an increase in HDL-C of 5% to 10%
was observed, irrespective of the dose or statin employed In
patients with reduced HDL-C levels (35 mg/dl) statins may differ in
their effects on HDL-C levels (Simvastatin >Atorvastatin)
Slide 64
Effects of Slatins on LDL-C Levels Statins lower LDL-C by 20%
to 55% depending on the dose and statin used Maximal effects on
plasma cholesterol levels are achieved within 7 to 10 days. The
statins are effective in almost all patients with high LDL-C
levels. The exception is patients with homozygous familial
hypercholesterolemia, the partial response in these patients is due
to a reduction in hepatic VLDL synthesis associated with the
inhibition of HMG-CoA reductase-mediated cholesterol synthesis
Nonlipid roles of statins Endothelial Function Plaque Stability
Inflammation Lipoprotein Oxidation Coagulation
Slide 69
Statins and Endothelial Function Statin therapy enhances
endothelial production of the vasodilator nitric oxide, leading to
improved endothelial function after a month of therapy
Slide 70
Statins and Plaque Stability. They reportedly inhibit monocyte
infiltration into the artery wall in a rabbit model Inhibit
macrophage secretion of matrix metalloproteinases in vitro modulate
the cellularity of the artery wall by inhibiting proliferation of
smooth muscle cells and enhancing apoptotic cell death
Slide 71
Statins and Inflammation Statins decreased the risk of CHD and
levels of C- reactive protein (CRP, an independent marker for
inflammation and high CHD risk) independently of cholesterol
lowering
Slide 72
Coagulation Statins reduce platelet aggregation reduce the
deposition of platelet thrombi in the porcine aorta model the
different statins have variable effects on fibrinogen levels
Slide 73
SECONDARY BENEFITS Bone metabolism Hypertension Heart failure
Dementia Cancer prevention Renal function Sepsis and
infections
Slide 74
Hepatotoxicity Elevation in hepatic transaminase to values
greater than three times the upper limit of normal Incidence as
great as 1% The incidence appeared to be dose related liver failure
one case per million person-years of use measure alanine
aminotransferase (ALT) at baseline and thereafter when clinically
indicated.
Slide 75
Patients taking 80-mg doses (or 40 mg of rosuvastatin) should
have their ALT checked after 3 months. If the ALT values are
normal, it is not necessary to repeal the ALT test unless
clinically indicated
Slide 76
Myopathy myopathy as any muscle disease myalgia as muscle ache
or weakness without increased serum CK levels myositis as muscle
symptoms with elevated CK levels rhabdomyolysis as muscle symptoms
with marked CK elevations (>10 times upper limit of normal
[ULN]) plus an elevated serum creatinine. (FDA) defines
rhabdomyolysis as organ damage, typically renal insufficiency, with
a CK level greater than 10,000 IU/L
Slide 77
Myopathy major adverse effect The incidence of myopathy is
quite low (~0.0 1%). but the risk of myopathy and rhabdomyolysis
increases in proportion to plasma statin concentrations Factors
inhibiting statin catabolism are associated with increased myopathy
risk, including advanced age (especially >80 years of age),
hepatic or renal dysfunction. perioperative periods. multisystem
disease (especially in association with diabetes mellitus), small
body size, and untreated hypothyroidism
Slide 78
RISK FACTORS FOR STATIN MYOPATHY conditions that increase
statin serum and muscle concentration factors that increase muscle
susceptibility to injury
Slide 79
Asymptomatic patients Routine surveillance of CK levels is not
required except in high-risk patients If CK measured CK < 5 ULN:
reassurance CK 5 -
The most serious complication of niacin therapy is
hepatotoxicity, and therapy should be accompanied by monitoring of
serum liver function tests therapy should be discontinued if
transaminases reach >3 times normal. Because hepatotoxicity
appears to be more common with sustained-release preparations of
niacin, the immediate-release form is preferred. Other side effects
of niacin therapy include impairment or worsening of glucose
tolerance and hyperuricemia.
Slide 88
The fibric acid derivatives clofibrate, gemfibrozil, and
fenofibrate lower plasma triglycerides by about 40% and increase
HDL-C levels by about 10% but have only minor effects on LDL-C.
These agents act by activating the (PPAR) a, a nuclear hormone
receptor that is expressed in the liver and other tissues. This
results in increased fatty acid oxidation, increased LPL synthesis,
and reduced expression of apo-CIII, all of which contribute to
lowering plasma triglycerides.
Slide 89
Side effects include gastrointestinal discomfort and possibly
an increased incidence of cholesterol gallstones (documented for
clofibrate). Fibric acid derivatives should be used with great
caution in the setting of renal insufficiency Fenofibrate, which
does not interfere with statin metabolism and has a much lower risk
of causing myopathy, is the preferred fibrate to use in combination
with a statin.
Slide 90
Omacor is prepared in capsule form containing a gram of oil,
which includes a total of 840 mg of EPA plus DHA. At the
recommended dosage of four capsules daily given to patients who
have triglycerides of 500-2000 mg/dL, Omacor lowers triglycerides
by about 50%, raises HDL-C by about 10%, lowers VLDL-C by about
40%, and raises LDL-C by about 50%. Overall the total
cholesterol-to-HDL- C ratio is reduced by about 20% and the
non-HDL-C is lowered by about 10%
Slide 91
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Chylomicronemia Syndrome Patients with the chylomicronemia
syndrome often present with acute pancreatitis and severe
hypertriglyceridemia (triglycerides >22.6 mm/L [2000 mg/dL]).
These patients should be treated with total fat restriction until
the triglyceride level falls to a safe range The goal is to
maintain the triglyceride level at less than 11.3 mm/L (1000 mg/dL)
and preferably less than 4.5 mm/L (400 mg/dL). such patients often
require a triglyceride-lowering drug, such as a fibrate or niacin,
to maintain the plasma triglyceride level in a range that prevents
subsequent episodes of pancreatitis