SM 125 Lipoprotein Metabolism and Pharmacology Flashcards
What are side effects of statins?
Hepatotoxicity up to 3x normal AST/ALT
Rhabdomyolysis or Myalgia of arm and leg muscles with elevated CK
What role does LCAT play?
Lecithin Cholesterol Acetyltransferase acts on pre-B-HDL to acylate Cholesterol, leading to internalization of Cholesterol esters and forming a cuboidal shape
LCAT is activated by binding to HDL surface and uses a Phospholipid as an Acyl donor
What is Cholesterol?
A sterol in the Eukaryotic membrane which maintains membrane fluidity and is a precursor to steroids and hormones
Free -OH
What is the fate of LDL?
LDL uses ApoB100 to bind LDLR in either the Liver or Peripheral tissues, allowing it to deliver Cholesterol and lower the amount of Cholesterol in the bloodstream
What are oxidized LDL and how do they form?
Oxidized LDL is a derivative of LDL that cannot be taken up using LDLR
Oxidized LDL is taken up by macrophages and results in the formation of foam cells and eventually Atherosclerosis
How are PCSK9 inhibitors administered?
IV, second line to statins
What is direct transport of HDL?
HDL binds to SR-B1 in the Liver and enters directly
What does LDL contain?
ApoB100 alone, and Cholesterol
What is indirect transport of HDL?
HDL is acted on by Cholesterol Ester Transfer Protein (CETP) to form LDL which enter the Liver via LDLR
What is LRP and what does it do?
LRP is Lipoprotein Receptor Protein; binds ApoE and ApoB48 on Chylomicron remnants
How are lipoproteins characterized?
They are characterized by differences in electrophoretic mobility, due to differences in size/charge ratio’s and density that arise from the relative amount of protein:lipid in their composition
How does Cholesterol flow through the Exogenous pathway?
Micelles in the small intestine are emulsified by Bile Acids
Micelles are then taken up into Enterocytes using the transporter NPC1L1
Enterocytes then package TG, Cholesterol, and Phospholipids into the Micelles and release them into Lymph ducts as Nascent Chylomicrons
What are the four major pathways of Cholesterol flux?
Cholesterol flux is primarily mediated by:
Exogenous Pathway (dietary intake) Endogenous Pathway (Liver production of VLDL) Reverse Cholesterol Transport (Peripheral to Liver) Enterohepatic Circulation (Recirculation of Bile)
How do nascent Chylomicrons enter circulation?
They are released by enterocytes into circulation at the Lymphatic duct and enter circulation using the left brachiocephalic vein
What is the Friedwald Equation?
Approximation used to derive LDL-c
0.2 * TG + HDL-c + LDL-c = TC
What should be done to lower High LDL-c?
Statin = first line
Second line varies = Ezetimibe or Bile Acids (poorly tolerated)
What are lipids and what is their common underlying feature?
Lipids are a group of heterogeneous compounds with varied structures
They are all insoluble in water
What statins are unaffected by CYP?
Pravastatin
How do Bile Acid sequestrants work?
They bind bile acids in the gut to prevent their reuptake and force Cholesterol to be used to replenish them, lowering Cholesterol in the Liver and inducing hepatocyte expression of LDLR to lower serum Cholesterol
Second line to statins
What lipoproteins do nascent Chylomicrons contain?
Nascent Chylomicrons contain Apo-B48 and Apo-A1
What are high intensity statins?
Statins that lower LDL-c by 50% or more
Atorvastatin 40 or 80mg/day
Rosuvastatin 20 or 40mg/day
What effects do Fibrates have?
Normal TG + Elevated LDL = lower LDL
Elevated TG + Normal LDL = lower TG + increase LDL
Always raises HDL
What is Familial Chylomicronemia Syndrome?
Due to a defiency in either Lipoprotein L or ApoC-II, which are needed for the hydrolysis of TG into FA
Leads to very high levels of Chylomicrons and high TG since they are unable to deliver FA
How does reverse Cholesterol transport progress?
ApoA1 produced by the Liver is lipidated to form pre-B-HDL, which is discoid in shape
Pre-B-HDL is acted on by LCAT to transfer esters to it’s Cholesterol groups, making them more hydrophobic and leading to internal aggregation that forms a spherical shape overall; direct or indirect transport of HDL ensues
What is Familial Hypertriglyceridemia?
Autosomal dominant, family history of overproduction of VLDL leading to high levels of TG
What should be done to lower high TG?
Check to make sure patient does not have DM or hypothyroidism
Fibrates and Omega-3 fatty acids to reduce risk of Pancreatitis
What are Free Fatty Acids?
A fatty acid chain that may be saturated or unsaturated
Carboxylic acid head group, ampiphathic
What is PCSK9 deficiency?
Deficiency of PCSK9 disinhibits LDLR expression, leading to elevated levels of LDLR on Hepatocytes and lowered LDL levels in the blood
What transports TG from Liver to tissues?
Chylomicrons and VLDL transport TG from Liver to tissues via LPL
What are Phospholipids?
Diverse and complex group of lipids with 2FA linked to a glycerol along with a phosphate and head group
What is a Cholesterol Ester?
Cholesterol with an ester that covers the Free -OH, less hydrophilic and more hydrophobic
What is the risk of elevated TG?
Pancreatitis, common in Familial Hypertriglyceridemia
What drug increases the toxicity of all statins?
Cyclosporine
What is enterohepatic circulation?
The recirculation of bile salts in the gut
Bile salts are formed from Cholesterol, and loss of bile salts uses up Cholesterol to reform them, so they are normally recycled
What levels of HDL, LDL, and TG are associated with disease?
High LDL, High TG, low HDL = disease
What is Apolipoprotein B deficiency?
Genetic disorder affecting ApoB resulting in elevated LDL-c since LDLR do not uptake LDL normally
Order the lipoprotein classes by size:
Small to large:
HDL < LDL < IDL < VLDL < Chylomicron Remnants < Chylomicrons
What is the mode of action of Ezetimibe?
Inhibits NPC1L1 in enterocytes to block reuptake of Cholesterol
Second line after statins
What is reverse Cholesterol transport?
The uptake of Cholesterol by HDL from peripheral sites and delivery to the Liver
What is Dysbetalipoproteinemia?
Defect in ApoE2 synthesis, an LDL cofactor, that prevents binding to Lipoprotein receptors
Results in accumulation of IDL that cannot be converted into LDL, increases risk of atherosclerosis
What groups do statins effect the most?
High risk groups gain the most benefit from statins
What statins are affected by CYP3A4?
ASL
Atorvastatin
Simvastatin
Lovastatin
What does LDL-c refer to?
LDL-c = LDL cholesterol = amount of Cholesterol and Cholesterol Ester found on LDL in the blood
What is the relationship between size and density in a lipoprotein?
Increasing size leads to decreasing density and vice versa
Why do PCSK9 inhibitors work?
PCSK9 inhibitors disinhibit LDLR expression, allowing the Liver to express more LDLR and take more LDL out of circulation to lower blood Cholesterol
What statins are affected by CYP2C9?
Fluvastatin
Describe the response to decreased Cholesterol in the Liver?
Decreased cholesterol is detected by SREBP
SREBP induces transcription of LDLR mRNA to upregulate LDLR
SREBP also induces PCSK9 to inhibit expression of LDLR
Overall LDLR is expressed, with some inhibition, to pull more LDL/Cholesterol out of the circulation
How do statins works?
Statins inhibit HMG CoA Reductase to inhibit Cholesterol synthesis, leading to more LDLR expression and lower amounts of cholesterol carrying LDL in the circulation
What are the clinical manifestations of Familial Hypercholesteremia?
TEPA
Tendon Xanthomas = bumps near Achilles tendon
Eyelid Xanthelasma = scrunched eyelinds
Premature Atherosclerosis
Arcus Corneae = white deposit in Iris
What is measured in clinic for Triglycerides?
Chylomicrons and VLDL
What is measured in clinic for LDL-c?
Chylomicron remnant, IDL, LDL
How does Cholesterol flow through the endogenous pathwway?
Liver produces VLDL which is metabolized essentially the same way as Chylomicrons, but produces LDL instead; also delivers FA as TG and Cholesterol to the tissues
How do VLDL deliver FA and Cholesterol to tissues?
VLDL also interacts with Lipoprotein Lipase in peripheral tissues using ApoC as a tissue-specific cofactor
VLDL’s deliver FA as TG and deliver Cholesterol
VLDL lose ApoC to form IDL
Why are lipids Amphipathic and what is the functional significance of this property?
Lipids are amphipathic due to having polar heads and hydrophobic tails
Allows them to create macromolecular complexes such as liposomes and micelles
What does grapefruit juice do?
Interferes with CYP 450
How are IDL formed?
IDL form after VLDL is acted on by Lipoprotein Lipase and loses ApoC
What are the side effects of PCSK9 inhibitors?
MDD
Myalgia
Delerium
Dementia
What are the components and structure of a lipoprotein?
Apolipoproteins, amphipathic surface and hydrophobic core containing hydrophobic molecules (FA, Cholesterol)
How do nascent Chylomicrons mature?
They are exposed to HDL in circulation and obtain ApoC and ApoE from the HDL
Where is NPC1L1 found and what does it do?
NPC1L1 is found in the enterocytes and mediates uptake of dietary cholesterol from the gut
What reaction is the rate limiting step of Cholesterol synthesis?
HMG CoA to Melavonate
Catalyzed by HMG CoA Reductase
What are the four major classes of lipids?
Free fatty acids, Triglycerides, Phospholipids, and Cholesterol
What are the three key enzymes to Lipoprotein transport?
Lipoprotein Lipase
Lechitin-cholesteroal Acyltransferase
Choseteryl Ester Transfer Protein
What are the risks for Rhabdomyolysis in statins?
Potentiated by drugs that inhibit CYP-3A4
What is PCSK9?
PCSK9 is expressed after SREBP senses a decrease in Hepatocyte intracellular Cholesterol concentration
PSCK9 inhibits expression of LDLR on Hepatocytes
What is the Lipoprotein Lipase and what is it’s cofactor?
Lipoprotein Lipase is an enzyme in peripheral tissues that recognizes ApoC as a cofactor on Chylomicrons
It is used to mediate tissue specificity for Chylomicron delivery and converts Triglycerides into Free FA
What do nascent VLDL contain and where are they made?
Nascent VLDL made in the Liver and released into circulation, where it interacts with HDL
Nascent VLDL = ApoC, ApoE, ApoB100
How are Triglycerides released from Chylomicrons?
Lipoprotein Lipase in peripheral tissues recognizes tissue-specific ApoC on mature Chylomicrons
ApoC is returned to HDL upon binding
Triglycerides in the Chylomicron are converted into free FA by Lipoprotein Lipase and taken up by the cell
What do Omega 3 fatty acids do and how do they work?
3 blocks V + B to Lower T
EPA blocks VLDL and ApoB synthesis in the Liver to decrease TG
How are TG “converted” to Cholesterol?
Each TG = 0.2 Cholesterol aka 5TG = 1 Cholesterol
What protein is mutated in Familial Hypercholesteremia?
LDL receptor is mutated leading to insufficient clearance of LDL particles
What transports Cholesterol from Liver to tissues?
LDL transports Cholesterol from Liver to tissues via LDLR as a breakdown product of VLDL
What is the fate of IDL?
IDL interacts with HDL in circulation to lose ApoE and form LDL
What is the fate of a Chylomicron remnant?
Chylomicron remnants form after a Chylomicron delivers Triglycerides to peripheral tissue
Chylomicron remnants use ApoE and ApoB48 to bind LRP in the Liver and re-enter the Liver
What is Familial Hypercholesteremia?
Genetic disorder arising from mutations in LDLR, haploinsufficiency leads to Heterozygotes (300mg/dL Cholesterol) and Homozygotes (1000mg/dL)
Approach to treating low HDL-c?
No evidence based therapy exists, can use Niacin
How do Fibrates works?
CLT AAH
Fibrates = PPARa agonists, primarily aim to lower TG levels, also raises HDL
Block ApoC-III to activate Lipoprotein Lipase and lower TG from VLDL
Activate ApoA-I and ApoA-II to increase HDL
What is ApoE2
An ApoE isoform that acts as an LDL cofactor, implicated in Dysbetalipoproteinemia
E3 = normal, E2 = abnormal; E2/E2 + second hit = disease
What drug class is used to lower LDL-c?
Statins are the first line for lowering LDL-c
What side effects and contraindications do Fibrates have?
GM
Side effects = gallstones and myopathy
Contraindications = renal or hepatic disease
What are Triglycerides?
3FA + glycerol backbone
What are the primary functions of lipoproteins?
They deliver TG as fuel and transport Cholesterol and Phospholipids
What is measured in clinic for HDL-c?
Pre-B-HDL, HDL3, HDL2
What is the goal of Niacin and how does it work?
Aims to lower TG by blocking Adipose TG mobilization and blocking Liver TG synthesis
May not actually work
What drugs are statins often combined with?
Bile Acid sequestrants and Ezetimibe
What is the mode of inheritance of Familial Hypercholesteremia?
Autosomal Dominant
What enzyme catalyzes the rate limiting step of Cholesterol synthesis?
HMG CoA Reductase
What is the hallmark feature of Familial Hypercholesteremia?
Premature atherosclerosis
