HDL and Cholesterol

I've already covered a bit of this here, but not very well, so here we go again!

Structure and function of cholesterol

See earlier post: Lipids- Cholesterol

The necessity of cholesterol becomes more apparent in deficiencies, such as in Smith-Lemli-Opitz syndrome. In this syndrome, there is a mutation in the DHCR7 gene which codes for 7-dehydrocholesterol reductase, the final enzyme required in the production of cholesterol. As such, people with Smith-Lemli-Opitz syndrome have insufficient cholesterol, and have a range of abnormalities ranging from microcephaly to limb malformations to congenital heart defects.

Cholesterol absorption and biosynthesis

Absorption

Absorption of dietary cholesterol is very poor, as plant sterols compete for the same transporters, and some cholesterol moves out of enterocytes and back into the gut lumen. Cholesterol enters cells through NPC1L1 transporters (cholesterol cannot diffuse across the plasma membrane very well). Once inside the cell, it can be converted to cholesterol ester and packaged into chylomicrons, as described here. Alternatively, cholesterol can move back into the gut lumen via ABCG5/8 channels or into HDL via ABCA1 channels.

Excretion

Excretion of cholesterol mainly occurs via the bile. Hepatocytes can convert cholesterol into bile acids, which enter bile through BSEP channels. Alternatively, cholesterol can enter the bile via ABCG5/8 channels. Not all cholesterol in the bile is excreted- a lot of it is reabsorbed.

Biosynthesis

Some cholesterol can also be synthesised by cells. The five major steps are as follows:

1. Acetyl-CoA converted to HMG-CoA via HMG-CoA synthase
2. HMG-CoA converted to mevalonate via HMG-CoA reductase. (This is the rate-limiting step, which is why it's targeted by statins.)
3. Mevalonate converted to isopentenyl pyrophosphate (IPP)
4. IPP converted to squalene
5. Squalene converted to cholesterol

Cholesterol homeostasis and regulation of cell cholesterol

As mentioned in my last post, entry of LDL causes downregulation of HMG CoA reductase, an increase in ACAT expression, and a decrease in LDL receptors. But how is cholesterol regulated?

Wonder no more! Cholesterol can be sensed by the SREBP protein, which is located in the membrane of the endoplasmic reticulum. When cholesterol levels decrease, SREBP is cleaved by SCAP, causing it to "bud off" from the ER and move to the Golgi and then into the nucleus. Once in the nucleus, it acts as a transcription factor, where it regulates HMG-CoA reductase expression. (Remember, HMG-CoA reductase is the limiting factor in cholesterol production!)

HDL formation and metabolism
Reverse cholesterol transport

HDL formation starts with nascent HDL, which is either secreted by the liver and intestine, or formed as a byproduct of chylomicron and VLDL metabolism. More specifically, nascent HDL is sometimes made up of the "surface remnants" from chylomicron and VLDL metabolism. Cells of the body have cholesterol ester hydrolase, which converts cholesterol ester to cholesterol, which moves out of cells and into HDL via ABCA1. HDL then converts cholesterol back to cholesterol ester via an enzyme called LCAT, which is activated by Apo-A1. When the cholesterol has been esterified, HDL becomes mature.

There are a couple of different fates of HDL. Firstly, cholesterol ester in HDL can be transferred between HDL and LDL via an enzyme called CETP. Alternatively, HDL can be taken up into the liver and adrenal glands by the SR-B1 receptor.

Why HDL is protective against atherosclerosis

HDL can protect against atherosclerosis in several ways:

• Inhibits recruitment of macrophages to arteries
• Inhibits arterial smooth muscle proliferation
• Inhibits arterial smooth muscle contraction (HDL increases NO production, causing vasodilation)
• Mediates transport of cholesterol from cells