Trait#70: Cholesterol and Ageing
Monday, June 08, 2020. Author FitnessGenes
Monday, June 08, 2020. Author FitnessGenes
CETP stands for cholesteryl ester transfer protein.
It is an enzyme involved in the transport of lipids (i.e. fats and cholesterol) in the bloodstream.
More specifically, CETP plays a key role in moving and exchanging fat (in the form of triglycerides) and cholesterol between different transport particles known as lipoproteins.
Studies suggest that variants of the CETP gene are linked to differences in blood lipid levels, risk of cardiovascular disease, aging and longevity.
Lipoproteins are particles that transport fats and cholesterol in the bloodstream.
As you may recall, we have different types of lipoproteins, which differ from one another in their size, density, lipid composition and sites of transport.
CETP plays a key role in the manufacture and regulation of some of these types of lipoprotein particles.
The main classes of lipoproteins include:
These are the largest lipoprotein particles and transport fat (in the form of triglycerides) from the intestine to be used by peripheral tissues. For example, triglycerides transported in chylomicrons can be stored in adipose tissue or used for energy by skeletal muscle.
These particles are formed after triglycerides have been removed from chylomicrons (described above) and used by peripheral tissues. Chylomicron remnants transport the remaining cholesterol and triglycerides back to liver to be further metabolised.
VLDL particles are produced by the liver and transport triglycerides from the liver to be used by peripheral tissues (e.g. skeletal muscle, adipose tissue). They are similar to chylomicrons, but transport triglycerides made by the liver rather than those absorbed from food in the intestine.
IDL particles are formed after triglycerides in VLDL particles have been removed and used by peripheral tissues. In this respect, IDL particles can be thought of as “VLDL remnants”. IDLs transport remaining cholesterol and triglycerides back to the liver to be further metabolised.
LDL particles are formed from VLDL and IDL particles, and predominantly carry cholesterol. Cholesterol is an important fat-like substance used to make cell membranes, hormones and key signalling molecules.
LDL particles transport cholesterol in the bloodstream to peripheral tissues, including skeletal muscle, adrenal glands, ovaries and testes. They also transport cholesterol to the liver.
The cholesterol contained within LDL particles may also be deposited within arterial linings. When this occurs, fatty, cholesterol-rich plaques (called atheromas) start to build up within arterial walls, causing narrowing of arteries and impaired blood flow to tissues. This process is called atherosclerosis, and is linked to heart attack, stroke and other cardiovascular disease.
On this note, high levels of LDL particles are linked to an increased risk of cardiovascular disease. For this reason, cholesterol carried within LDL (known as LDL cholesterol) is often known as “bad cholesterol.”
As the name suggests, HDLs are the most dense lipoprotein particles. They are rich in cholesterol and phospholipids (another type of lipid).
HDLs are responsible for a process called reverse cholesterol transport. This involves transporting cholesterol from peripheral tissues (including arterial linings) to the liver to be removed or further metabolised. In this respect, in contrast to LDL, HDL may help to prevent the build up of fatty plaques and protect against cardiovascular disease.
On this note, studies suggest that higher levels of HDL particles are associated with a decreased risk of cardiovascular disease. For this reason, cholesterol contained within HDL (i.e. HDL cholesterol) is often termed “good cholesterol”.
Cholesteryl ester transfer protein (CETP), as its name implies, acts to transfer cholesterol and triglycerides between different lipoproteins.
Under normal conditions, the CETP enzyme moves triglycerides from LDL, IDL and VLDL particles and transfers them to HDL particles. At the same time, CETP transfers cholesterol from HDL to LDL, IDL and VLDL particles.
The overall effect of CETP is to decrease the amount of cholesterol carried in HDL particles – in other words, it reduces levels of “good” HDL cholesterol.
Given this role, some drugs have been invented to inhibit CETP, thereby increasing HDL levels, which may in turn help to prevent atherosclerosis. Despite this approach working in theory, clinical trials have failed to demonstrate the effectiveness of CETP inhibitors.
The CETP enzyme is encoded by the CETP gene.
Variants of this gene are shown to have an effect on the activity and blood concentration of CETP enzyme, which, in turn, alters the size and blood levels of various lipoprotein particles.
A SNP (rs5882) within the CETP gene creates two variants / alleles – the “A” allele and the “G” allele.
Studies suggest that people inheriting two copies of the “G” allele (i.e. those with the GG genotype) have significantly lower blood levels and decreased activity of the CETP enzyme.
Furthermore, this decrease in CETP levels / activity is shown to affect lipoprotein size. Individuals with the GG genotype have significantly larger HDL and LDL particles.
This finding is interesting because the size of lipoprotein particles is thought to affect a person’s risk of developing atherosclerosis and cardiovascular disease.
Recall that cholesterol carried in LDL particles (i.e. “bad” LDL cholesterol) may be deposited in fatty plaques in arterial walls, leading to narrowing of arteries. Larger LDL particles, by virtue of their size, are less likely to penetrate into arterial walls and form fatty plaques.
Larger HDL particles have also been linked to improved cardiovascular health, although the mechanism behind this is unclear.
Given the above, CETP variants that lead to larger LDL and HDL lipoprotein particles may confer a reduced risk of developing cardiovascular diseases such as heart attack and stroke.
Another SNP in the CETP gene (rs708272) creates “C” and “T” alleles. These are also known as B1 and B2 alleles, respectively.
Some studies suggest that the 'T' (B2) allele is associated with reduced CETP enzyme activity and significantly higher levels of “good” HDL cholesterol.
Similarly, another SNP (rs1864163) within the CETP gene gives rise to two further gene variants: the “G” allele and the “A” allele. Studies suggest that inheriting one or two copies of the G allele is associated with higher levels of “good” HDL cholesterol.
High HDL levels are thought to be beneficial as they may protect against the deposition of cholesterol in arteries and therefore reduce the risk of atherosclerosis and cardiovascular disease.
Conversely, low levels of HDL cholesterol are associated with an increased risk of cardiovascular disease.
Interestingly, some CETP gene variants are also linked to a slower ageing process and increased longevity / lifespan.
On this note, one study looked at Ashkenazi Jewish subjects with very high longevity (subjects had an average age of 98.2 years old), as well as their offspring.
Compared to a control group, the GG genotype (with respect to the rs5882 SNP) was significantly overrepresented in the higher longevity subjects. For example, 24.8% of higher longevity group had the GG genotype, compared to just 8.6% of controls.
It is possible that the increased longevity conferred by the GG genotype is due to a decreased risk and incidence of cardiovascular disease and dementia, although more research is needed in this area.
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