Term
| What are the major lipid "players" in atherosclerotic lesion formation? |
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Definition
1) TAG (dietary fats used for energy storage)
2) Phospholipids (membranes)
3) Cholesterol and Cholesteryl esters (membranes) |
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Term
| What are the basic features of lipoproteins? |
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Definition
Water-soluble carriers of hydrophobic elements (TGA or cholesterol) between tissues.
1) Inner droplet of neutral (water-insoluble core lipids_
- Usually triglycerides and cholesteryl esters
2) Solubilizing surface layer of phospholipids and unesterified cholesterol
3) Apolipoproteins attached to outer layer through lipophillic domains
- Apo A on HDL is protective
- Apo B on atherogenic lipoproteins |
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Term
| What are the 4 major uses of lipid-soluble components transported by Lipoproteins? |
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Definition
1) Energy metabolism
2) Cell components (phospholipids and un-esterified cholesterol)
3) Hormone precursors
4) Eicosanoid precursors for Thromboxane and Prostacycline |
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Term
| What is the exogenous pathway of lipid transport? |
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Definition
Dietary/Chylomicron
1) Dietary cholesterol is absorbed and delivered to liver via intestinally-derived Apo B(48) containing lipoproteins called CHYLOMICRONS
2) Some absorbed cholesterol delivered to extra-hepatic tissues via chylomicrons (plaques), and the rest is eliminated
**biliary reabsorption returns some to liver, so elimination is incomplete
3) Biliary system brings liver cholesterol to the intestine, where is is absorbed via NPC1L1 transporter. |
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Term
| What are Chylomicrons and how are do influence lipid metabolism? |
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Definition
TG-rich, Apo B lipoproteins that are synthesized in liver and carry dietary fat to peripheral tissue
1) Long chain FA are re-esterified into TG in gut and then transferred to Chylomicrons
2) Apo C-II activates lipoprotein lipase, which hydrolyzes TG in chylomicron
3) Chylomicron remnant is taken up via apoB48/remnant receptors in liver
**Also can infiltrate endothelium ad contribute to plaque formation** |
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Term
| What is the endogenous pathway of lipid transport? |
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Definition
Liver synthesized lipids
1) Endogenous cholesterol produced in liver is secreted into circulation via hepatically-derived apoB 100 lipoproteins
** VLDL remnants, IDL and LDL are apoB100**
2) Lipoproteins penetrate arterial endothelium (plaques)
3) LDL is taken up by liver via LDL receptor, and cholesterol is excreted from liver as free cholesterol or bile acids via biliary system. |
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Term
| What does apoB 100-containing VLDL influence lipid metabolism? |
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Definition
VLDL (TG-rich, hepatically-derived)
1) Takes endogenous TGA in liver and enters circulation
2) Acquires apoC-II, apoC-III, apoE and cholesteryl ester from HDL
3) apoC-II activates LPL and TGA are hydrolyzed
4) Fatty acids are complex with albumin and taken to muscle (energy), adipose (storage) and liver (metabolism)
5) apo proteins given back to HDL, while TG-poor VLDL remnant or IDL is further processed (**can become subendothelial plaque**)
6) Remnant IDL particle can be taken up by apoE/remnant receptors or can become LDL via hepatic TG lipase |
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Term
| What does hepatic triglyceride lipase have to do with lipid metabolism? |
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Definition
After TG-rich VLDL undergoes hydrolysis via LPL, and becomes TG-poor IDL/remnant particle, that particle can either be
1) Taken up by apoE/remnant receptors in liver
2) Converted to LDL via hepatic TG lipase
**LDL is major cholesterol carrier** |
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Term
| What does apoB 100-containing LDL influence lipid metabolism? |
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Definition
Product of VLDL metabolism (hepatic TG lipase) which is 50% cholesterol, delivering it to peripheral tissues for biosynthesis and steroid hormone production.
1) VLDL converted to LDL
2) LDL cholesterol delivery and removal via apoB 100 receptors on liver
** If LDL cannot be taken up (familial hypercholesterolemia) you get tendonous xanthomas and corneal arcus** |
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Term
| Why might a patient present with tendonous xanthomas and corneal arcus? |
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Definition
| Familial Hypercholesterolemia due to absent LDL receptor |
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Term
| What are the basic steps of HDL metabolism? |
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Definition
HDL is made in intestine and liver (smallest) and is important for reverse cholesterol transport, cholesterol removal from peripheral cells and delivery of cholesterol to liver.
1) Secreted in discoidal form from liver/gut, and becomes spherical as it acquires cholesterol from tissues and circulation (lecithin:cholesterol acyl transferase or LCAT)
2) Reverse cholesterol transport
- Peripheral cholesterol taken up by HDL (ABCA1)
- cholesterol is esterified (LCAT)
- esterified cholesterol transfered to LDL in exchange for TG (CETP), where it is taken up via LDL receptor |
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Term
| Which of the three artery structural components are the site of atherosclerosis? |
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Definition
Remember, Monkeberg is medial sclerosis, and Atherosclerosis in INTIMA
1) Adventitia (blood and nerve supply to artery, itself)
2) Media (smooth muscle with vascular tone)
3) Intima (BM covered by endothelium, regulating hemostasis, thrombosis, vascular tone and permeability). |
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Term
| What happens to the vascular endothelium in atherosclerosis early on? |
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Definition
1) Damaged integrity increases permeability
2) Atherogenic lipoproteins (apoB) enter, as due monocytes
- Monocytes become macrophages, which eat oxidized LDL and become cholesterol-rich foam cells.
**FATTY STREAK FORMATION**
3) Diminished vasodilation and compromised hemodynamic control |
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Term
| How do fatty streaks form? |
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Definition
1) Damaged endothelium are more permeable, so lipoproteins enter
2) Monocytes migrate, become macrophages and eat up oxidized LDL, forming foam cells.
3) Foam cells accumulate, forming fatty streak |
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Term
| What are the major steps of Plaque formation? |
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Definition
1) Fatty streak composed of foam cells grows and forms lipid core, which becomes isolated by fibrous cap
2) Depending upon cap sturdiness (collagen, proteoglycans and activated smooth muscle cells), the plaque may rupture
3) As lipids continue to accumulate in core, apoptosis occurs and plaque can become de-stabalized.
**Oxidized LDL contains cholesterol ester, which causes macrophages to secrete cytokines (IL-6, CRP, TNFa) leading to vascular inflammation and weakening of cap**
**Macrophages also secrete MMPs and collagenases that will weaken cap** |
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Term
| Why do you see vascular inflammation in atheromatous plaques? |
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Definition
1) Oxidized LDL contains cholesterol ester, which causes macrophages to secrete cytokines (IL-6, CRP, TNFa)
2) Cytokines lead to vascular inflammation and weakening of cap
**Macrophages also secrete MMPs and collagenases that will weaken cap** |
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Term
Why provide lipid care management? Whats the goal?
Who is high-risk? |
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Definition
Reduce LDL to lower risk of CHD (keep it <100 mg/dL), via lifestyle changes or drugs
- High risk is presence of CVD with 1) diabetes, 2) smoking, 3) HDL-C <40mg/dL and 4) ACS |
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Term
| What are the options for treatment of Hyperlipidemia? |
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Definition
1) Statins are 1st line
- HMG-coA reductase inhibitors in liver
- causes LDL receptor up-regulation by hepatocytes and increased removal of apoE and B lipoproteins in circulation
- will ALSO get rid of VLDL and IDL remnants and control TG!
2) If Statin not tolerate (5-10%)
- Niacin or Bile Acid Resin |
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Term
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Definition
HMG-coA reductase inhibitors that
1) Reduce cholesterol synthesis in liver, thereby reducing plasma cholesterol
2) Increase LDL-R, so there is more uptake of non-HDL particles as well (deals with TG) |
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Term
True or False:
Statins should be limited to patients with moderate TG elevation (150-300 mg/DL). |
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Definition
True! Remember, this is really a cholesterol treatment
Above this and you should
1) treat the underlying cause (diabetes or hypothyroidism) or
2)use TG-lowering drugs (niacin, fibrates and fish oils) |
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Term
| What is the time course of statin effects? |
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Definition
1) Restoration of endothelial function (weeks to months)
2) Reduced inflammation (few months)
3) Stabilization of vulnerable plaque (several years)
** This is where cardiac events are reduced |
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Term
| What are the major adverse effects of Statin use? |
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Definition
95% safe
Headache, fatigue, Myalgia (are they in renal failure?), flu-like and GI
** Liver enzyme elevation is a lie!** |
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Term
True or False:
Statin therapy should be discontinued in the presence of elevated liver enzymes? |
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Definition
Depends, but probably false, as this is a NORMAL occurence
you WOULD discontinue if this was Niacin treatment |
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Term
How do each of the following intestinal-acting agents work to reduce cholesterol?
1. Bile acid sequestrates
2) Plant stanols/sterols
3) Ezetimibe |
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Definition
1) Increased clearance of LDL by liver
- Inhibit bile acid reabsorption in ileum causing hepatic deficiency. More bile acids are then made from cholesterol, which is replenished by LDL chylomicron uptake from plasma
2) Displace cholesterol from micelles, preventing uptake at brush border and reducing amount transported to liver. Reduced delivery increases clearance by liver.
3) Inhibits micellar cholesterol uptake (sterol transporter inhibitor) in intestinal epithelium, thereby reducing amount transported to liver.
Compensatory increase in liver clearance. |
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Term
| When might you use Ezetimibe? |
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Definition
Add it to ongoing stable stain therapy in patients not at goal to reduce LDL-C.
Selective Cholesterol Absorption Inhibitor (CAI) that prevents intestinal absorption of cholesterol by inhibiting sterol transporter (DOES NOT EFFECT VITAMIN UPTAKE) |
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Term
| How do Bile Acid resins such as Colesevelam, Colestipol and Cholestyramine lower plasma cholesterol levels? |
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Definition
1) Bind bile acids in intestine, reduced enterohepatic recirculation of bile acids.
2) Liver- 7-alpha hydroxylase is up-reglated to convert more cholesterol in hepatocyte into bile acids
3) Decrease in cholesterol enhances LDL-R expression, which increases LDL and VLDL remnant removal
** Sometimes ineffective, since liver also makes more TG and cholesterol ** |
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Term
| Why might you prescribe Colesevevelam instead of Colestipol or Cholestyramine to treat high LDL-C? |
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Definition
1) TG
- Older agents may increase TG
2) Drug interactions
- Older agents bind other negatively charged drugs |
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Term
| Why would you prescribe Nicotinic acid (Niacin) to lower LDL-C? How does it work? |
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Definition
1) Best option to increase HDL-C
- reduces LDL-C and coronary events as well
- available in immediate and extended-release
2) Inhibits lipoprotein synthesis and decreases VLDL production in liver.
- Less apoB means less VLDL means less LDL
- Increases apoA, so more HDL
Long
1) Inhibits peripheral mobilization of free fatty acids, thereby reducing hepatic synthesis of TG and secretion of VLDL |
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Term
| What are the major limitations of Niacin use to increase HDL-C and lower LDL-C? |
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Definition
DONT GIVE IF
1) Active liver disease (or unexplained elevation in LFT)
2) Peptic ulcer disease
Side Effects
1) Flush/Itch/Headache
2) Hepatotoxicity and GI (in sustained-release)
3) Peptic ulcers
4) Hyperglycemia and reduced insulin sensitivity (no diabetics please!) |
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Term
| What drugs are useful to ADD to a stable statin? |
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Definition
1) BAR like Colesevelam (as long as GI is ok)
2) Niacin
May give all 3 in familial hypercholesterolemia |
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Term
| How can you most effectively treat mixed hyperlipidemia? |
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Definition
1) Start with lifestyle change and then reduce LDL-C
2) Achieve non-HDL-C goal by adding a fibrate, fish oil or niacin |
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Term
| Why might you prescribe a fish oil? How does it work? |
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Definition
1) Adjunctive therapy to diet hypertriglyceridemia (Type IV and V) with statins or other LDL-C-lowering drugs in mixed hyperlipidemia
2) Limits VLDL TG release!
- Activates DGAT, Phosphatidic acid (PA) and Hormone-sensitive lipase to
a) stimulate beta-oxidation
b) increase phospholipid synthesis
c) cause apo B degradation |
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Term
| Why might you prescribe fibric acid? How does it work? |
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Definition
** Muscle toxicity is a worry when combined with statin**
1) Adjunctive to diet hypertriglyceridemia (IV or V) in combined hyperlipidemia (IIb) with LOW HDL-C WHO DO NOT RESPOND TO NIACIN
2) Increase peripheral lipolysis and decrease hepatic TG production |
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