Ok, in preparation for takeoff, the captain has illuminated the fasten seatbelts sign ....
Originally Posted by ForgotMyOldUsername
Let me start off by plagiarizing myself a bit ... I posted some of this in other threads.
How do we get triglycerides in plasma?
Dietary fats are not absorbed into the blood stream as other nutrients are. This is principally due to the fact that fats are hydrophobic ( i.e. not soluble in water). Instead, fats are taken up by the lymphatic system and packaged into chylomicrons, which sequester the fats inside of a lipoprotein shell which is itself soluble in water, whereupon the chylomicron fat delivery vehicles are set loose for distribution via the bloodstream.
The only source of triglycerides in circulation is the diet. While the body is certainly capable of synthesizing fatty acids from carbohydrates via de novo lipogenesis, when it does so, it creates NEFA, non-esterified fatty acids, or more simply, fatty acids that are not attached to a glycerol backbone a.k.a. our old friend tri ( three fatty acids) glycerides ( attached to a glycerol backbone. )
Ok, got it, so now that we have triglycerides in plasma, how do we get at them?
As I mentioned, triglycerides need to be enveloped in a water soluble lipoprotein shell in order to dissolve in plasma and circulate, the chylomicron delivery vehicles. So, naturally, in order to get at the contents of the lipoprotein, you need some mechanism to break through the shell. That mechanism is an enzyme known as lipoprotein lipase (LPL). In biochemistry, any enzyme that breaks things down ends with an "ase" suffix, so as the name tells us, lipoprotein lipase takes lipoprotein lipids and breaks them down into free fatty acids and glycerol.
Many tissues express LPL, but the one we are interested in here is adipose LPL. Adipose tissue secretes LPL which travels and binds to the endothelial lining of the blood vessels where it can act on unsuspecting chylomicrons that stumble into its lair. When a hapless chylomicron happens along, it gets acted upon by this LPL which produces glycerol and free fatty acids in the immediate vicinity of the adipose cell.
Nature abhors a gradient
Many things in metabolism are driven by concentration gradients. This means that molecules naturally move from an area of high concentration to an area of low concentration. In order for this to happen in cells, the cell membrane needs to be permeable to the particular molecule. If the membrane is permeable, the molecules will move as expected. If the membrane is not permeable, then water will tend to move from the area of low concentration to the area of high concentration in order to dilute it, and thereby equilibrate the effective concentration across the membrane.
Adipose cell membranes are permeable to fatty acids, so, whether there will be a net movement of fatty acids into or out of the cell depends primarily on whether there is a higher concentration of fatty acids on the inside or outside of the cell membrane.
What controls the level of NEFA inside an adipose cell?
If you were to examine the contents of an adipose cell, you would observe that there is a small pool of free fatty acids, and a substantial storage pool consisting of a triglyceride droplet. There is always a baseline level of triglyceride synthesis going on in the adipose tissue where free fatty acids are combined with a glycerol molecule to form triglycerides. This process is known as acylation, and the more technically correct name for triglycerides is triacyglycerides, a term that you may have seen in the scientific literature.
There is also a baseline of free fatty acids being generated within the adipose cell via hydrolysis by a lipase that acts upon the triglyceride droplet to create free fatty acids and a glycerol phosphate molecule within the adipose cell. This is hormone sensitive lipase (HSL), the action of which is supressed by insulin, hence the hormone sensitive bit.
There is another actor on this stage, acylation stimulating protein, or ASP. The function of this enzyme is all in the name. What it does is increases the rate of acylation within adipose cells. Because the formation of new triacylglycerides requires a glycerol backbone, ASP also stimulates adipose cell uptake of glucose from the blood stream in order to synthesize new glycerol.
In general, then, the level of NEFA inside an adipose cell is determined by the balance between acylation and triglyceride hydrolysis. Anything that increases acylation will decrease the free fatty acid pool, and anything that increases hydrolysis will increase the fatty acid pool.
Putting it all togetherSo how does hormonal and nutritional status affect all of these moving parts? Well, insulin tends to increase the activity of adipose LPL while correspondingly decreasing the activity of HSL. This results in an increase in FFA concentration on the outside of an adipose cell, and as hydrolysis is suppressed within the adipose cell, the net result is a concentration gradient with a lower concentration within the adipose cell. So we will see a net movement of FFA into the adipose cell. Insulin also causes GLUT4 glucose transporters to translocate to the adipose cell membrane where they increase the uptake of glucose into the cell to enable increased acylation, i.e. triglyceride synthesis. So, increased insulin == increased triacylglyceride synthesis.
But, adipose LPL activity is also stimulated by the presence of chylomicrons, there is no need for insulin. So the mere fact that you have eaten some fats will result in an increase in the concentration of free fatty acids outside of adipose tissue. Because there is no insulin, there will not be any significant change in the activity of HSL, but then we need to pay attention to what ASP is doing, and when we look over, we notice that the activity of ASP is stimulated by the mere presence of chylomicrons ... again, there is no insulin whatsoever required for this to happen.
So, we eat pure fat, this results in no appreciable insulin response, but we will obviously absorb our meal and increase circulating chylomicrons for several hours ( peak levels of chylomicrons will occur within 3 - 5 hours ). The elevated chylomicron levels stimulate adipose LPL and ASP. As a result, there is an increased concentration of FFAs in the vicinity of adipose tissue, along with a concomitant decrease in the adipose FFA pool due to increased acylation as driven by ASP. Fat deposition ... no insulin required!
Of course, the mother of all fat deposition meals is one that elevates insulin _and_ chylomicrons, because now you will have ASP and insulin working in tandem to increase the concentration gradient. And what sort of meals result in elevated insulin and chylomicron levels? Pretty much any meal you are likely to eat, short of settling in for movie night with a tub of lard and a spoon.
Taking a look at all of these mechanisms it almost seems as though the human body is designed / evolved to be very good at storing fat ... it is almost as though our very survival depended on it! Perish the thought!