Case 20- strokes Flashcards
Renshaw cell
Inhibitory interneurone
Classification of lipids: Simple lipids - esters of fatty acids with alcohols
- Fats & oils: Esters of fatty acids with glycerol. Fats –solid, oil-liquid
- Waxes: esters of fatty acids with alcohols other than glycerol. Aliphatic or alicyclic.
Complex lipids
Esters of fatty acids with alcohol containing other groups such as protein, carbohydrate.
• Phospholipids: contain phosphoric acid and a nitrogenous base e.g. glycerophospholipid – lecithin or sphingophospholipid – sphingomyelin
• Glycolipids: contains fatty acids, carbohydrates and nitrogenous base
• Lipoproteins: macromolecular complexes of lipid and proteins
• Other: sulfolipid, aminolipid, liposaccharide. Derived lipids
Lipoproteins as ‘Delivery vans’
Lipoproteins carry 1) Apolipoproteins 2) Free cholesterol 3) Cholesterol esters 4) Phosphlipids 5) Free soluble vitamines • Cholesterol-Functions= bile acids, steroid hormones, cell membrane • Triglycerides- energy production, energy storage
Apolipoprotein roles
- Structural components of lipoproteins- ApoB100, apoB48, apoA1
- Ligand Binding, receptor recognition- ApoB100, apoE
- Activation/ inhibition of lipolysis- ApoCII, apoCIII
- Cholesterol Efflux- ApoAI, apoAII, apoAIV
- Polymorphic forms- ApoE, apoaIV, apoB
- Undefined physiological role- Apo(a), apoJ, apok
Where the Apoliproproteins are found
- Cholesterol and triglyceride are transported in lipoproteins
- Apolipoproteins govern lipoprotein metabolism
- ApoB is the major apolipoprotein of VLDL, IDL and LDL
- ApoB48 is found only in lipoproteins of intestinal origin
- ApoA1 is the major apolipoprotein of HDL
- Apolipoproteins A, C and E move between HDL and TRLs
Apolipoproteins found in Chylomicrons
C-III
B-48= exclusive to chylomicrons and their remnants
Apolipoproteins found in VLDL
B-100
Apolipoproteins found in IDL
B-100
Apolipoproteins in LDL
B-100
Apolipoproteins found in HDL
A-I
LDLR, HTGL
LDLR- low density lipoprotein receptor
HTGL-hepatic triglyceride lipase
LRP
LDL receptor-related protein. It has diverse biological roles which include functions in lipid metabolism, and also in the homeostasis of proteinases and proteinase inhibitors, cellular entry of viruses and toxins, activation of lysosomal enzymes, cellular signal transduction, and neurotransmission.
The exogenous lipoprotein pathway
- Fat and cholesterol which have been absorbed from the gastrointestinal tract are assembled to form chylomicrons.
- The chylomicrons then travel in the bloodstream to peripheral tissues, the first part of their journey is through the lymph it then enters the circulation at the thoracic duct
- In the peripheral tissues (e.g. adipose tissues) chylomicrons release their fats when they meet tissue expressing lipoprotein lipase (LPL). This allows fats to be absorbed in the form of fatty acids and glycerol. The heart receives TG first
- After unloading their fats, chylomicrons become smaller and are then known as chylomicron remnants.
- Empty HDL is produced as a byproduct of steps 3 and 4.
- Chylomicron remnants then travel to the liver and are removed by the binding of apoE to their remnant receptor. Supplies TG for energy use and storage
The endogenous lipoprotein pathway
- Fat and cholesterol arriving at the liver are repackaged into VLDLs.
- VLDLs enter the bloodstream between meals and travel to the peripheral tissues.
- VLDLs meet tissues expressing lipoprotein lipase (e.g. muscle and adipose tissue) and release their glycerol and fatty acids, it is then known as an IDL.
- Empty HDL is produced as a byproduct (which can then collect LDL from the periphery).
- IDLs are absorbed from the blood by the liver.
- IDLs are then broken down by hepatic lipase into LDLs (triglycerides are removed in this process).
- LDLs have relatively high cholesterol content whilst having minimal fatty acids and glycerol content.
- LDL circulates and is absorbed by various tissues via binding to LDL receptors.
- Excess LDL is absorbed by the liver via LDL receptors through ApoB100
ABCA1
ATP-binding cassette transporter, also known as the cholesterol/phospholipid efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. It is defective in patients with Tangier disease and familial HDL deficiency. These patients cannot form HDL, and therefore have a defect in reverse cholesterol transport.
SR-B1
Scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues.
HTGL, RLP, LDLR
HTGL = hepatic triglyceride lipase
RLP – remnant lipoprotein
LDLR = low density lipoprotein receptor
LRP
LDL receptor-related protein It has diverse biological roles which include functions in lipid metabolism, and also in the homeostasis of proteinases and proteinase inhibitors, cellular entry of viruses and toxins, activation of lysosomal enzymes, cellular signal transduction, and neurotransmission.
Recycling LDL receptors
You can recycle LDL receptors for reuse. LDL is released at low pH in the lysosome allowing LDLR to be recycled while LDL is completely broken down. PCSK9 prevents release of LDL so both LDL and LDLR are broken down in the lysosome so LDLR numbers are reduced
Cholesterol transport pathway
- The Exogenous pathway delivers triglyceride from the gut to adipose tissue and muscle, and cholesterol to the liver
- The Endogenous pathway delivers triglyceride and cholesterol from the liver to adipose tissue, muscle and other tissues
- Lipoprotein lipase (LPL) offloads triglyceride into the tissues
- The liver is responsible for clearance of remaining cholesterol and triglyceride from the plasma via enzymes and receptors
- ApoB and ApoE are the major ligands for the hepatic receptors
- PCSK9 is an important regulator of LDLR
Reverse cholesterol transport pathway
- When there is too much cholesterol in the peripheral tissues the ABCA1 receptor is activated.
- HDL then interacts with this receptor and collects cholesterol returning it to the liver, it is then excreted as bile. An empty HDL molecule is then released
- This pathway can help prevent the development of atherosclerosis.
SREBP
In humans there are two SREBP genes, SREBP1 and SREBP2. SREBP1 is expressed primarily in the liver while SREBP2 is ubiquitously expressed
Intracellular cholesterol homeostasis
- SREBPs are synthesized as ER membrane proteins where they bind with SREBP cleavage-activating protein (SCAP), an important cholesterol sensor and transporter.
- This association with SCAP retains SREBP in the ER. Under low sterol conditions the SREBP-SCAP complex is transported to the Golgi where proteolytic cleavage of SREBP releases the N-terminal bHLH domain, allowing increased expression of target gene e.g. squalene synthase and HMG-Co A reductase. More cholesterol is also taken up by the cells, reduced production of VLDL and bile acids. Decreased levels of cholesterol in hepatocytes
- In increased cholesterol- The sterol-sensing domain of HMG-CoA reductase regulates its association with INSIG in response to levels of lanosterol, a cholesterol precursor.
- INSIG binds the E3-ubiquitin ligase, gp78, which polyubiquitinates HMG-CoA reductase resulting in its degradation. Thus, sterols regulate the retention of SREBPs in the ER and the degradation of HMG-CoA reductase.
