Regulation of cholesterol synthesis

previously we talked about the by synthesis of cholesterol and we saw how complicated this process actually is well now we're going to switch to the regulation of cholesterol synthesis and we'll see that this actually is not very complicated so the most important thing you have to take away from this lesson is the regulation of cholesterol since synthesis occurs at the level of the rate-limiting enzyme HMG co-reductase so as we'll talk about all these different regulatory methods remember this fact to increase the production of cholesterol we have to increase the expression of HMG co-reductase to decrease the production of cholesterol we have to decrease the expression of hmg-coa reductase so let's begin with sterile dependent regulation so let's suppose within our body specifically within the liver cells we have low levels of cholesterol if we have low levels of cholesterol that stimulates the proteolytic cleavage of an important transcription factor off the ER membrane so this is the membrane of the endoplasmic reticulum and attached to this membrane on the cytosol Excite is a protein called srebp which stands for sterile regulatory element binding protein so when this transcription factor comes off it becomes activated and that quickly moves into the nucleus of the cell and in the nucleus of the cell it binds onto a section of the DNA known as SR e sterile regulatory element and once bound it up regulates the expression of the mRNA that codes for HMG co-reductase so the mRNA exits the nucleus it goes onto the ribosomes the ribosomes essentially create that enzyme and that we have more enzyme to create cholesterol and that increases the amount of cholesterol inside the cell when we have high levels of cholesterol so when we synthesize enough this creates a negative feedback loop so essentially their intermediates in the cholesterol biosynthesis pathway as well as cholesterol itself that moves back here and inhibits the proteolytic cleavage of the sterile regulatory element binding protein and so this will decrease the production of cholesterol so this is the major way by which we can regulate cholesterol synthesis now let's move on and talk about the sterile independent regulation so sterile dependent means we're dealing with a binding protein so we're dealing with the stale regulatory element binding protein but sterile independent regulation means we don't deal with this sterile protein so hmg-coa reductase is an enzyme that functions most effectively if it's not modified but if we modified with phosphorylation for example this will decrease its activity making it inactive so if we have a lot of ATP within our cell the cell has enough energy to synthesize cholesterol but what happens if we decrease the supply of ATP if we have low if we have low levels of ATP inside the liver cell then all the ATP has been converted to a MP and a MP what it does is it binds unto certain protein kinases and then activates those protein kinases and so by activating protein kinases they can phosphorylate HMG co-reductase and that can make it inactive so if we have low energy levels low levels of ATP in the cell that means we're now going to produce cholesterol and that makes sense because if we have low levels of ATP we want to use the remaining ATP for other more important processes than producing cholesterol conversely if we have high levels of ATP then we're gonna stimulate the dephosphorylation of this by these enzymes we call phosphatases and so if we have a lot of ATP the liver cells we're going to produce a lot of cholesterol then we can also have regulation at the level of hormones specifically the two hormones are insulin and glucagon and glucagon so in the fed state so after we eat a meal rich in proteins and fats for example insulin is going to be released and insulin there's a bunch things for example insulin stimulate cells to reuptake glucose from the blood but it also actually acts on liver cells and other cells in the body to up regulate the expression of HMG co-reductase so that the cells can produce more cholesterol so why would we want to produce more cholesterol well if we intake a meal that is rich in fat we actually have to be able to absorb that fat and transport that fat in the blood and that means the livers has to produce lipoproteins and one component of lipoproteins is cholesterol so essentially when insulin levels are high after the fed state then we're producing a lot of cholesterol and that allows us to produce lipoproteins that can carry the fat that we absorb from erudite conversely if we're in the fasting state then glucagon levels are high and this will turn off the expression of HMG co-reductase thereby decreasing the production of cholesterol so glucagon stimulates cholesterol synthesis on insulin stimulates the synthesis of cholesterol but glucagon decreases it and then the final thing I will talk about our medications and the medications or a focus our our our statins so statins are essentially molecules that resemble h mg co h and so what that means is statins are competitive inhibitors of hmg-coa reductase so statins are given to patients who have a condition known as hyperlipidemia so essentially high levels of fats such as cholesterol and by giving patients statins we block the activity of hmg-coa reductase that decreases the production of cholesterol within our liver cells and that stimulates something called the reverse cholesterol pathway so we'll talk more about this later on but very briefly it causes the liver to actually absorb more cholesterol out of the blood and into the liver and that decreases the levels of cholesterol and other lipoproteins within the blood

Channel: AK LECTURES

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Keywords: regulation of cholesterol synthesis, cholesterol synthesis, sterol regulatory element binding protein, SREBP, control of cholesterol synthesis

Id: xkHaVYfJEP0

Length: 6min 35sec (395 seconds)

Published: Thu Jun 27 2019