Lipid Metabolism

Question 1

lipids are soluble/ insoluble in water?

Answer 1

insoluble

Question 2

functions of lipids?

Answer 2

• membrane biogenesis
• membrane integrity
• energy sources
• precursors for hormones and signalling molecules

Question 3

what two things do lipoproteins transport in the blood?

Answer 3

cholesterol esters

triglycerides

Question 4

structure of lipoprotein

Answer 4

hydrophobic core (containing esterified cholesterol and triglycerides)
hydrophilic coat (a monolayer of amphipathic cholesterol (NOT cholesterol ester), phospholipids, and one or more apoproteins)

Question 5

what are the major lipoproteins?

Answer 5

• HDL (contain ApoA1 and ApoA2)
• LDL (contain ApoB100)
• VLDL (contain ApoB100)
• Chylomicrons (ApoB48)

Question 6

Where are chylomicrons formed?

Answer 6

intestinal cells

They transport dietary triglycerides (the exogenous pathway)

Question 7

Where are VLDL particles formed?

Answer 7

Liver cells

They transport triglycerides synthesised in that organ (the endogenous pathway)

Question 8

What is the life cycle of ApoB containing liposomes?

Answer 8

• Assembly: with apoB100 in the liver, and apoB48 in the intestine
• Intravascular metabolism: involving hydrolysis of the triglyceride core (lipoprotein lipase attaches triglyceride - generating 3 fatty acids and glycerol - which can be uptaken into muscle or fat cells)
• Receptor mediated clearance

Question 9

how do triglycerides cross the intestinal wall to be absorbed?

Answer 9

they must first be broken down by lipase. The monoglycerides and free fatty acids produced can then readily diffuse across enterocyte membrane. Once inside, re-esterification occurs so triglyceride is synthesised again

Question 10

how does cholesterol get absorbed into the enterocytes?

Answer 10

It requires a specific transport protein (NPC1L1) - this is a drug target - can be inhibited to limit cholesterol absorption. Once absorbed, cholesterol is esterified to cholesterol ester.

Question 11

where does most cholesterol in the body come from?

Answer 11

75% from bile (produced in the liver)

25% from diet

Question 12

Once triglycerides and cholesterol have entered enterocytes, what happens to assemble them into chylomicrons?

Answer 12

• triglycerides come together to give tiny triglyceride droplets - which are then coated with ApoB48 (a protein).
• This new chylomicron becomes larger by triglyceride addition (lipidation) facilitated by enzyme MTP.
• cholesterol ester is added too
• Then a second apoprotein (apoA1) is added
• chylomicron exocytoses out of cell and into lymphatics
• carried to systemic circulation via thoracic duct

Question 13

how are VLDL particles assembled?

Answer 13

assembled in liver hepatocytes. Trigyceride sources are from breakdown of adipose tissue (in fasting state) or from the liver (de novo synthesis) in fed state. MTP lipidates ApoB100 and then you get newly formed VLDLs. These increase in size by further triglyceride incorporation.

Question 14

what must happen before chylomicrons and VLDL particles can deliver their triglycerides and cholesterol to adipose and muscle tissue?

Answer 14

-Activation
This occurs by the transfer of ApoC2 from HDL particles. The ApoC2 is incorporated into the chylomicron/ VLDL shell, and allows chylomicrons and VLDL to bind to endothelium of vasculature (to an enzyme Lipoprotein lipase - which is particularly found in endothelium of vasculature - especially in vasculature supplying fat and muscle cells)

Question 15

What happens in the intravascular metabolism of ApoB-containing lipoproteins?

Answer 15

LPL enzyme is associated to endothelium of capillaries supplying the adipose and muscle tissue. ApoC2 facilitates binding of chylomicrons and VLDL to LPL. LPL hydrolyses core triglycerides to free fatty acids and glycerol - which enter tissues. The particles are now depleted of triglycerides (but still contain cholesterol esters) and are called chylomicron and VLDL remnants. As the ratio of triglycerides changes, particles unbind from LPL.

Question 16

what happens in the clearance of ApoB-containing lipoproteins?

Answer 16

chylomicrons and VLDL remnants dissociate from LPL. ApoC2 (from HDL) goes back to HDL in exchange for ApoE - which acts as a high affinity ligand for specific receptor in the liver - which will clear the remnant particles from the plasma. The remnants now return to the liver. All ApoB48, and half of Apo100 remnants are further metabolised to remove any triglyceride content. The other 50% of Apo100 remnants lose further triglyceride through hepatic lipase, becoming smaller and enriched in cholesterol ester. Via IDLs, they become LDL particles which lack ApoE and retain solely ApoB100.

Question 17

how does clearance of LDL particles take place?

Answer 17

dependent on LDL receptor expressed by liver and other tissues. Clearance by liver is most important. Cellular uptake of LDL particles occurs via receptor-mediated endocytosis. Within the cell, cholesterol is released from cholesterol ester by hydrolysis. Released cholesterol causes: inhibition of HMG CoA reductase (the rate limiting step in de novo synthesis), down regulation of LDL receptor expression, storage of cholesterol as cholesterol ester.

Question 18

what initiates atherosclerosis?

Answer 18

dysfunction and injury to the endothelium of blood vessels (risk factors are diabetes, high BP, smoking)

Question 19

Outline the progression f atherosclerosis

Answer 19

-uptake of LDL into intima of artery (from the blood). LDL is then oxidised to ATHEROGENIC oxidised LDL (OXLDL)
-migration of monocytes across endothelium into intima where they become macrophages
-uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a fatty streak (an early event in atherogenesis)
-release of inflammatory substances from various cell types, causing division and proliferation of smooth muscle cells into the intima and the deposition of collagen
-formation of atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
SO, LDL is BAD cholesterol.

Question 20

why is HDL good?

Answer 20

• it removes excess cholesterol from cells by transporting it in plasma to the liver. The liver can eliminate cholesterol by secreting it as bile, or using it to synthesise bile salts.
• HDL is formed mainly in the liver, initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-B-HDL)
• disc-like pre-B-HDL matures in plasma to spherical a-HDL as surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
• mature HDL accepts excess cholesterol from plasma membranes of cells (e.g. macrophages) and delivers cholesterol to the liver (this is reverse cholesterol transport)

Question 21

Mature HDL accepts excess cholesterol from cells (e.g. macrophages) and delivers cholesterol to the liver. (Reverse cholesterol transport). What are the two ways in which it does this?

Answer 21

• HDL reaching the liver interacts with scavenger receptors which allow transfer of cholesterol and cholesterol ester into hepatocytes.
• In the plasma, CETP (cholesterol ester transfer protein) mediates transfer of cholesterol esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver. In unloading HDL - more cholesterol binding sites are available.

Question 22

what is dyslipidaemia?

Answer 22

elevation of plasma cholesterol, triglycerides, or both, or a low HDL level that contributes to the development of atherosclerosis. Causes may be primary (genetic/ diet) or secondary (consequence of type 2 diabetes/ alcoholism/ liver disease)