In class we talked about the formation of VLDL lipoproteins in the liver. The as
ID: 177154 • Letter: I
Question
In class we talked about the formation of VLDL lipoproteins in the liver. The assembly of VLDL particles within the liver involves a protein called microsomal triglyceride transfer protein (MTP), which is essential for the assembly of apolipoprotein B (apo-B) containing lipoproteins. Known inhibition of MTP prevents hepatic VLDL secretion by preventing VLDL production. Given this effect, drugs targeting MTP are of interest as potential drugs for hyperlipidemia (a condition with elevated levels of lipid and/or lipoproteins).
1a) Based on your understanding of relevant pathways involving VLDL, explain the basis of MTP inhibition as a hyperlipidemia drug. Would you expect LDL levels in the blood to increase or decrease? Why?
Explanation / Answer
VLDL or very low density lipoproteins are those fatty acids which easily precipitate out in the blood and form insoluble aggregates of cholestrol when combined with appropriate conjugation moleucles. This increases the blood cholestrol levels and requires clinical attention. Anti-hyperlipidemia drugs are generally used to treat such disorders. These drugs are based upon the concept that the enzyme MTP is absolutely required for generation of VLDL in the body by assemly and aggregation of apolipoprotein B. Thus, any drug which will inhibit MTP function will directly lead to inhibition of VLDL formation and release from the liver.
Technically, the MTP enzyme resides on the surface of rough endoplasmic reticulum. During translation, the small lipid globules are transferred in an assembled form to apolipoprotein B. This precursor apoliporptien B fuses with a triglyceride droplet to give rise to a nascent VLDL molecule. Drugs targettin anti hyperlidemia by MTP inhibition halt this process at stage 1 and prevent release of small lipid globules with apolipoprotein B.
On the contrary, LDL receptors are also involved in synthesis and release of VLDL. So, drugs targetting VLDL decrement will also lead to decline in LDL levels in the blood.
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