lipid lowering drugs

• what is an artheroma?


  plaque deposited on the innermost layer of systemic artery walls.
• what does artheroscerosis mean?

  Atherosclerosis is a chronic inflammatory disease of the arteries 
• what is arteriosclerosis?


  vascular disease characterized by thickening, hardening and remodelling of the arterial wall 
• what is arterioloscerosis?


  hardening/hyalinisation of the arterioles
• what two things can artherosclerosis progress into?

  • thombus formation
  • stenosis
• what are the potential problems with stenosis?

  • stenosis

  MI -> angina -> dysrhythmia/heart failure

  Peripheral arterial disease -> intermittent claudication
• what is meant by claudication?

  Claudication refers to muscle pain due to lack of oxygen that's triggered by activity and relieved by rest. Symptoms include the following: Pain, ache, discomfort or fatigue in muscles every time those muscles are used.
• how do statins affect the formation of plaques/ fatty streaks?

  statins inhibit HMG CoA reductase which is needed for the production of cholesterol -> cholesterol accumulations make up fatty streaks/ plaques
• cholesterol is amphipathic and present in PL bilayer and regulates fluidity and permeability, they are also seen in lipids rafts, what are these?

  Lipid rafts are dynamic assemblies of proteins and lipids that float freely within the liquid-disordered bilayer of cellular membranes  Rafts are small platforms, composed of sphingolipids and cholesterol regulate membrane function
• cholesterol is the synthetic precursor to...

  • steroid hormones (estrogen, testosterone, progesterone)
  • bile salts
  • vitamin D
• triglycerides = 3 fatty acids + glycerol

  (tri-esters)
• holoenzyme = apoprotein + co-factor
• apolipoproteins bind to lipids to form lipoproteins (package of lipids and proteins) which facillitate the transport of lipids in aq plasma
• list 5 exaples of lipoproteins

  • chylomicrons
  • IDL
  • HDL
  • LDL
  • VLDL
• what is the function of chylomicron?


  Transport dietary triglycerides from the intestines to various tissues for storage or energy use.
• what is the function of LDL?


  Often termed "bad cholesterol," LDL transports cholesterol from the liver to cells throughout the body. High levels of LDL are associated with an increased risk of atherosclerosis and heart disease.
• what is the function of IDL?

  precursor to LDL
• what is the function of VLDL?

  • Transport endogenous triglycerides synthesized in the liver to various tissues.
  • VLDL is a precursor to LDL.
• what is the function of HDL?


  • reverse cholesterol transport
  • Often termed "good cholesterol," HDL scavenges excess cholesterol from cells and transports it back to the liver for excretion.
  • High levels of HDL are associated with a reduced risk of heart disease.
• what are the two apoproteins to know? which lipoproteins are they found in?

  apoprotein B -> single copy in VLDVL, IDL, LDL (STRSS in the receptor region ) so only one LDL-R binding site

  apoprotein E -> multiple copies in VLDL, IDL but NOT LDL
• what is the LDL-R? where is it found?

  receptor that allows for binding with LDL, which is the major cholesterol transporting lipoprotein, then transported into the cell by endocytosis
• what is the difference between type 1 and 2 familial hypercholesterolaemia

  FH1 - there is a mutation in the LDL-R receptor -> reduced expression -> reduced affinity for LDL -> reduced uptake of LDL -> high levels of LDL in the bloodstream

  FH2 - there is a mutation in the ApoB gene turning STRSS into STOSS -> prevents the binding of of LDL to the LDL-R
• explain the process of cholesterol uptake in the cell


  1. circulating LDL
  2. the mooring of LDL particles by the LDL-R in coated pits
  3. the endocytosis/ invagination and pinching off of the coated vesicles
  4. fusion of the vesicle then gives rise to an endosome (with the LDL) and dissociates from the LDL-R
  5. LDL-R is recycled back onto the surface of the cell
  6. LDL delivered to a lysosome
  7. cholesteryl ester is cleaved -> becomes cholesterol and used for membrane synthesis or converted into steroid hormones or bile acids
  8. cholesterol uptake inhibits the cholesterol production of the cell

  
• why do mutations in LDL-R or Apoproteins cause hyperlipidemia?

  internalisation of the LDL is dependent on the mooring of the apoprotein on the LDL onto the LDL-R, if there is a mutation it affects the interaction between the two -> insufficient binding -> increased LDL levels
• where does the lipid travel in the body? what are the main transport pathways for cholesterol/lipids?

  1. from the gut to the liver
  2. from the liver to body cells
  3. from body cells to the liver
  4. between the gut and the liver
• describe how cholesterol is transported from the gut to the liver?

  • from the gut via the lymph to the liver
  • fat is absorbed
  • packaged into chylomicron
  • converted from cholesterol to cholesterol esters so it can be transported to the liver and into the endogenous pathway or for bile acids
• why is cholesterol converted into cholesteryl esters?

  Cholesterol is present as unesterified (free) and esterified portions in the body fluids (1). Free cholesterol is biologically active and has cytotoxic effects whereas cholesteryl ester (CE) is protective form for storage in the cells and transporting in plasma 
• describe the endogenous pathway in lipid/cholesterol transport in the body

  • this is from the liver to the body
  • deliver cholesterol and Triglycerides to cells
  • liver -> VLDL -> IDL -> LDL
  • as the LDL gets used up the size of the lipoprotein shinks and there is decreased lipoprotein density
• describe the pathway from the body to the liver

  • 'reverse colesterol transport'
  • via ApoA and ABCA1 receptor HDL takes up excess cholesterol
  • delivered to the liver by binding to Scavenger Receptor
• from the liver to the gut and back


  • via enterohepatic circulation
  • bile acid synthesis needs alot of cholesterol
  • cholesterol -> can be synthesised de novo, from the blood (LDL) or recycled from the enterohepatic circulation
• how is cholesterol synthesised (pathway of cholesterol synthesis with the enzymes named), which enzyme do statins target

  here

  
• what are the 4 sources of cholesterol recycling for hepatic synthesis of bile acids?

  • synthesis by the liver de novo
  • uptake of LDL by LDL-R
  • uptake of HDL by SCARB1
  • absorption of bile acids from the gut by the enterohepatic circulation

  
• list possible lipid lowering drugs you could use for dyslipidemia

  • Statins
  • PCSK9 inhibitors (MAB & siRNA)
  • PPAR agonists (fibrates)
  • colestyramine
  • ezetimibe
  • bempedoic acid
  • nicotinic acid
  • Icosapent ethyl (EPA, Fish oil)
• hyperlipidemia - higher than expected levels of LDL/lipids/cholesterol
• dyslipidemia - imbalance of lipids in the blood
• outline the different types of atherosclerosis and outline their development


  1. adaptive intimal thickening
  2. xanthoma
  3. pathological intimal thickening with lipid pools
  4. fibroatheroma (with necrotic core)
  5. fibrocalcific plaque