What is CETP?

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.

KEY POINTS

• CETP (cholesterol ester transfer protein) is an enzyme that regulates the transport and levels of cholesterol in the bloodstream.
• CETP gene variants affect blood lipid levels and aging.

What are lipoproteins?

Lipoproteins are particles that transport fats and cholesterol in the bloodstream.

We previously encountered lipoprotein particles in the APOA5 and triglycerides, APOA2 and saturated fat, and APOE, physical and mental health traits.

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:

Chylomicrons

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.

Chylomicron remnants

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 (Very Low Density Lipoproteins)

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 (Intermediate Density Lipoproteins)

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 (Low density Lipoproteins)

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.”

HDL (High density lipoproteins)

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”.

KEY POINTS

• Lipoproteins are particles that transport fat (in the form of triglycerides) and cholesterol in the bloodstream.
• LDL (Low density lipoprotein) particles transport cholesterol to peripheral tissues and may deposit cholesterol into arterial linings.
• LDL cholesterol is considered to be "bad" cholesterol.
• HDL (High density lipoprotein) particles transport cholesterol away from peripheral tissues and arterial linings to the liver.
• HDL cholesterol is considered to be "good" cholesterol.

What does the CETP enzyme do to lipoproteins?

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.

KEY POINTS

• CETP transfers triglycerides to HDL particles from LDL, IDL and VLDL particles.
• CETP also transfers cholesterol from HDL particles to LDL, IDL and VLDL particles.
• Lower CETP activity is linked to higher levels of "good" HDL cholesterol.

How do CETP gene variants affect lipoproteins?

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.

Lipoprotein size

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.

HDL levels

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.

KEY POINTS

• CETP gene variants affect the activity and blood levels of the CETP enzyme.
• Lower CETP activity / level is associated with larger LDL and HDL particles, which are less likely to cause narrowing of arteries and may confer a lower risk of  cardiovascular disease.
• Lower CETP activity / level is associated with higher blood levels of "good" HDL cholesterol.
• Higher levels of HDL cholesterol are associated with a reduced risk of cardiovascular disease.
• This trait looks at several SNPs that affect the activity of CETP and HDL levels, including: rs5882, rs708272 and rs1864163.

How do CETP gene variants affect longevity?

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.

KEY POINTS

• The 'G' allele of the CETP gene created by the rs5882 SNP is associated with increased longevity.
• Inheriting two copies of the G allele is linked to exceptional longevity.
• The "G" allele may also reduce the risk of dementia.

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