Hyperlipidemia Flashcards
chylomicrons - apolipoproteins, origin, and cargo
*apolipoproteins: Apo-B48, Apo-C-II, and Apo-E
*origin: small intestine → lymphatics
*cargo: triglycerides > cholesterol
VLDL - apolipoproteins, origin, and cargo
*apolipoproteins: Apo-B100, Apo-C-II, Apo-E
*origin: liver
*cargo: triglycerides > cholesterol
IDL - apolipoproteins, origin, and cargo
*apolipoproteins: Apo-B100, Apo-C-II, Apo-E
*origin: liver (more so a remnant of VLDL after it unloads some of its triglycerides)
*cargo: triglycerides/cholesterol
LDL - apolipoproteins, origin, and cargo
*apolipoproteins: Apo-B100
*origin: liver
*cargo: cholesterol
HDL - apolipoproteins, origin, and cargo
*apolipoproteins: Apo-A-1, Apo-C-II, Apo-E
*origin: liver
*cargo: cholesterol
apolipoprotein A-1 (Apo A-I)
*structural protein for HDL
*activates LCAT enzyme
apolipoprotein B-48 (Apo-B48)
*structural protein for chlyomicrons
apolipoprotein B-100 (Apo-B100)
*structural protein for VLDL, IDL, LDL
*binds LDL receptor
apolipoprotein C-II (Apo C-II)
*co-factor for LPL (lipoprotein lipase)
*Apo C-II enables LPL to unload triglycerides to tissues that need it for energy
apolipoprotein E (Apo-E)
*ligand for binding to LDL receptor & LDL-like receptors
*helps particles get back to the liver to be broken down and remade into VLDL
lipoprotein lipase (LPL)
*AN ENZYME THAT PRODUCES HYDROLYSIS IN LOW-DENISTY LIPOPROTEINS TO TURN THEM INTO GLYCEROL TO BE RELEASED IN THE MUSCLE
*expressed on endothelial cells in the heart, muscle, and adipose tissue
*has dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake
*LPL isozymes are regulated differently depending on the tissue:
-the form that is in adipocytes is activated by insulin
-the form that is in muscle & myocardium is activated by glucagon & adrenaline
exogenous cholesterol pathway (how we absorb & use dietary fats, lipids, and cholesterol)
*dietary fats are absorbed from the intestines & packaged into chylomicrons, which enter the circulation through the thoracic duct
*chylomicrons help to deliver triglycerides to tissues for energy
lifecycle of chylomicrons
- dietary fats are absorbed in the small intestine and packaged into chylomicrons (Apo-B48 is attached)
- HDL in the bloodstream donates Apo-E and Apo-CII to the chylomicron
- mature chylomicrons travel through circulation and deposit triglycerides to muscles & adipose tissue to use for energy
- after delivering a significant amount of triglycerides, the chylomicron remnant returns to the liver
how do chylomicrons deliver triglycerides to muscle, myocardium, and adipose tissue?
- when one of these tissues is in need of energy, it expresses lipoprotein lipase (LPL) on its endothelial cells
- chylomicrons have Apo C-II, which interacts with the LPL receptors
- this interaction allows the chylomicrons to donate triglycerides to that tissue
- once the chylomicron has used up its reserve of Apo C-II, the chylomicron remnant uses Apo-E to return to the liver
- the chylomicron remnant is repackaged in the liver as VLDL
endogenous cholesterol pathway (how the liver packages lipids & cholesterol)
*liver produces VLDL, which delivers triglycerides to tissues
*as triglycerides are delivered to tissues, the particles get much smaller
*when the particle contains almost all cholesterol and few little triglyceride, it has become an LDL particle
VLDL (Apo-B100) lifecycle
- tissues in need of energy express lipoprotein lipase (LPL) on their surface
- VLDL particles have Apo C-II, which interacts with LPL receptors
- this interaction allows VLDL particles to donate triglycerides to that tissue
- as the VLDL particle donates triglycerides, it becomes IDL
- IDL continues to donate triglycerides until it has used up its Apo C-II and no more triglycerides are left to donate
- at this point, the particle is LDL (contains only cholesterol & only has Apo B100)
LDL receptor - overview
*LDL particle binds to LDL-receptor → receptor-mediated endocytosis (brings the LDL particle into the cell)
*inside the cell, endosomes combine and break down the lipid particles
*the receptor itself is recycled and returns to the cell surface, where it can bind another LDL particle
LDL receptor & PCSK-9
*if the cell does not need any more cholesterol, it produces & secretes PCSK-9
*PCSK-9 binds to the cell’s LDL receptors
*when the LDL particles bind to the PCSK-9-bound LDL receptors, they are brought into the cell via receptor-mediated endocytosis (like normal)
*however, the LDL receptors are then BROKEN DOWN (not recycled to the cell surface) so that there are no more LDL receptors on the cell surface
classical LDL receptor
*located on cell membranes of most tissues in the body, but the MAJORITY ARE FOUND IN THE LIVER
*binds apolipoprotein B-100 and Apo-E
*Apo-E binds LDL receptors with 20x affinity than Apo-B100
*therefore, it is more difficult for the LDL particles (which only have Apo-B100) to return to the liver compared to VLDL and IDL particles (which also have Apo-E)
LDL-related protein-1 (LRP-1)
*acts as a scavenger receptor for remnant lipid particles
*binds Apo-E
*located in liver & nervous system
reverse cholesterol transport (how free cholesterol finds its way back to the liver) - detailed
- HDL has Apo-A1, which activates the enzyme LCAT
- LCAT (lecithin-cholesterol acyltransferase) CONVERTS FREE CHOLESTEROL INTO CHOLESTERYL ESTER (a more hydrophobic form of cholesterol), which is then sequestered into the core of a lipoprotein particle, particularly HDL
- CETP (cholesteryl ester transfer protein) facilitates transport of cholesteryl esters & triglycerides between lipoproteins:
-CETP enables HDL to give its cholesterol to lipoproteins that will go back to the liver (VLDL, IDL)
-this enables HDL to remain in the periphery & scavenge more free cholesterol
reverse cholesterol transport (SIMPLE)
- HDL uses Apo-A1 to activate LCAT
- LCAT converts free cholesterol into cholesteryl ester
- HDL takes up the free cholesterol
- CETP (activated by LCAT) transfers cholesterol from HDL to VLDL and IDL
- VLDL & IDL return the cholesterol to the liver, while HDL remains in the periphery to scavenge for more free cholesterol
inhibition of HMG-CoA reductase (part of the cholesterol synthesis pathway)
results in:
1. a build-up of HMG-CoA (the substrate of the enzyme)
AND
2. a decrease in mevalonic acid (the product of the enzyme)
hyperlipidemia - defined
*an increase in lipids in the blood
*hypercholesterolemia is a type of hyperlipidemia, but not all hyperlipidemias have increased LDL cholesterol
causes of hyperlipidemia
*diet
*hypothyroidism
*nephrotic syndrome
*anorexia nervosa
*obstructive liver disease
*obesity
*diabetes mellitus
*pregnancy
*acute hepatitis
*SLE
*AIDS (protease inhibitors)
Friedewald Equation for measuring LDL levels
*LDL = (total cholesterol - 0.2) x (triglycerides - HDL)
*LDL is not directly measured, but rather it is calculated
*note - cannot calculate LDL if triglycerides are > 400 mg/dl
appearances of various increased lipoproteins in serum
*increased chylomicrons → creamy top layer
*increased LDL → clear
*increased VLDL/IDL → turbid
type I hyperlipoproteinemia (familial hyperchylomicronemia)
*defects can be any of the following:
-lipoprotein lipase (LPL) deficiency
-familial Apo-CII deficiency
-circulating inhibitor of LPL
*increased particle = CHYLOMICRONS
*lab finding = increased triglycerides
*look out for pancreatitis!
type I hyperlipoproteinemia (familial hyperchylomicronemia) - pathophysiology
*by inhibiting LPL, the chylomicron is unable to unload its triglyceride-rich content
*the VLDL which is made also cannot unload its triglycerides
*result = INCREASED CHYLOMICRONS & INCREASED TRIGLYCERIDES
type IIa hyperlipoproteinemia (familial hypercholesterolemia)
*defect: defective LDL receptor
*increased particle = LDL
*lab findings = increased LDL, normal triglycerides
type IIa hyperlipoproteinemia (familial hypercholesterolemia) - pathophysiology
*by having a defective LDL receptor, LDL builds up
*note that VLDL and IDL do not build up because hepatic lipase converts them to LDL
dermatologic manifestations of hypercholesterolemia (type IIa hyperlipoproteinemia)
*xanthelasmas
*tendinous xanthomas
*corneal arcus
xanthelesmas
*plaques or nodules composed of lipid-laden histiocytes in the EYELIDS
*associated with FAMILIAL HYPERCHOLESTEROLEMIA (type IIa hyperlipoproteinemia)
tendinous xanthomas
*lipid deposits in tendons, especially Achilles tendon & finger extensors
*associated with FAMILIAL HYPERCHOLESTEROLEMIA (type IIa hyperlipoproteinemia)
corneal arcus
*lipid deposits in corneas
*common in older adults (arcus senilis) but appears earlier in life with hypercholesterolemia
*associated with FAMILIAL HYPERCHOLESTEROLEMIA (type IIa hyperlipoproteinemia)
type IIb hyperlipoproteinemia (familial combined hypercholesterolemia / hyperlipidemia)
*defect: defective/inhibited LDL receptor WITH increased apolipoprotein B100 production
*increased particles = LDL and VLDL
*lab findings = increased LDL and increased triglycerides
type IIb hyperlipoproteinemia (familial combined hypercholesterolemia / hyperlipidemia) - pathophysiology
*by having a defective LDL receptor & increased Apo-B100, the VLDL, IDL, and LDL all build up
*VLDL/IDL build up because hepatic lipase is overwhelmed and can’t keep up in converting them to LDL
type III hyperlipoproteinemia (familial dysbetalipoproteinemia)
*defect: defective apolipoprotein E related to larger particles
*increased particles = IDL, VLDL, and chylomicrons
*lab findings = increased triglycerides, increased total cholesterol
dermatologic manifestations of dysbetalipoproteinemia (type III hyperlipoproteinemia)
*tubo-eruptive xanthomas
*palmar xanthomas
tubo-eruptive xanthomas
*reddish bunos that appear suddenly over elbows, forearms, trunk, legs, extensor digitorum tendons, or buttocks
*associated with FAMILIAL DYSBETALIPOPROTEINEMIA (type III hyperlipoproteinemia)
palmar xanthomas
*soft yellow plaques/nodules containing deposits of lipoproteins on the creases of the PALMS
*associated with FAMILIAL DYSBETALIPOPROTEINEMIA (type III hyperlipoproteinemia)
type IV hyperlipoproteinemia (familial hyperlipidemia)
*defect: decreased removal of VLDL/excess VLDL production
*increased particle = VLDL
*lab finding = increased triglycerides
type V hyperlipoproteinemia (familial hypertriglyceridemia)
*defect: increased VLDL production & decreased LPL activity
*increased particles = VLDL & chylomicrons
*lab findings = increased triglycerides
*look out for pancreatitis!
apolipoprotein B48 defects
*if impairs production of chylomicrons, then leads to fat/cholesterol absorption problems:
-steatorrhea
-failure to thrive
-muscle wasting
-neurological issues/coordination
-fat soluble vitamin deficiencies
apolipoprotein B100 defects
*if significant impairment of B100’s ability to bind LDL receptor, then may mimic familial hypercholesterolemia with high levels of LDL
CETP (cholesterol ester transfer protein) defects
*rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis
*a CETP inhibitor (Ancetropib) causes substantial increase in HDL and modest decline in LDL
*trans fats increase CETP activity
LCAT (lecithin-cholesterol acyltransferase) defects
*impairment of LCAT leads to cholesterol deposits in the corneas, kidney, and other tissues and organs
*decreased LCAT concentration and activity are associated with decreased HDL levels but not with increased atherosclerosis
LDL levels and risk of MI/CAD
*LOWER LDL levels are BETTER
*increasing LDL levels are associated with increased risk for MI and CAD
LDL particle size & risk of atherosclerosis
*among individuals with the same LDL levels, the number of LDL particles and the size vary
*SMALLER LDL PARTICLES are associated with MORE ATHEROSCLEROSIS (it is easier for these particles to enter the arterial lining following injury)
HDL levels & risk of MI
*individuals with high LDL PLUS LOW HDL are at the highest risk of developing an MI
lipoprotein(a)
*sits on the surface of the LDL particle
*associated with a significantly INCREASED risk of atherosclerosis and coronary artery disease
*Lp(a) contributes to the process of atherogenesis: because of its structural similarity to plasminogen & tPA, competitive inhibition leads to reduced fibrinolysis
*must be very aggressive in lowering LDL
statins - site of action
*competitive inhibition of HMG-CoA REDUCTASE in the liver (part of the cholesterol synthesis pathway)
*2 groups: hydrophilic and lipophilic
effects of statins on LDL receptors & plasma LDL levels
*statins inhibit cholesterol synthesis → liver perceives a deficiency and expresses MORE LDL RECEPTORS to obtain cholesterol
*by increasing LDL receptors, LDL binds to the receptors and goes into the liver → LOWER PLASMA LEVELS OF LDL CHOLESTEROL
atorvastatin
*example of LIPOPHILIC statin
rosuvastatin
*example of HYDROPHILIC statin
pleiotropic effects of statins
*increased platelet function
*decreased coagulation
*decreased inflammation
*decreased free radicals
*increased endothelial function
*increased collagen
*DECREASED LDL
*INCREASED HDL
PCSK-9 inhibitors - MOA
*inhibition of PSCK-9 → LDL receptors return to the cell surface, rather than being degraded by lysosomes
*hence, LDL receptors increase → LDL levels DECREASE
*example = evolocumab
bempedoic acid - MOA
*a first-in-class small molecular inhibitor of ATP-citrate lyase (which produces acetyl-CoA)
non-pharmacologic considerations to lower lipids: DIETARY FAT/CHOLESTEROL
*monounsaturated fats: lowers LDL, raises HDL
*polyunsaturated fats: lowers LDL, raises HDL
*saturated fats: raises both LDL and HDL
*trans fats: raises LDL
non-pharmacologic considerations to lower lipids: EXERCISE
*exercise is one of the few ways to RAISE HDL
