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Cholesterol serves a myriad of functions in the human body. Cholesterol exists in several forms, the most important of which are low-density lipoproteins (LDL) cholesterol and high-density lipoproteins (HDL) cholesterol.
LDL cholesterol has the tendency to stick to the walls of the blood vessels when the level of cholesterol in the body becomes too high. This leads to formation of plaques within the blood vessels (Atherosclerosis) that can narrow the lumen of the vessels. This results in compromise of blood flow to the vital organs, thereby increasing the risk of heart attack and stroke.
HDL cholesterol, unlike LDL cholesterol, has been known for its ability to remove the plaques from the blood vessels and thus play a protective role for the heart. Shocking new evidence suggests that pharmaceutical interventions to increase the concentration of HDL cholesterol have resulted in harmful effects of HDL cholesterol on the heart.
This study was carried out at the University of Pennsylvania and was led by Dr. Daniel J. Rader. This research was co-funded by NIH’s National Center for Research Resources (NCRR) and National Center for Advancing Translational Sciences (NCATS). The study was subsequently published in Science.
The basic aim of the study was to find out the association between HDL cholesterol and cardiovascular diseases. Trials were carried out on 328 participants with very high HDL cholesterol levels of about 107 mg/dl and 398 subjects with extremely low HDL cholesterol levels of about 30 mg/dl on an average.
HDL Cholesterol Doing More Harm than Good
The study unearthed a genetic variant within the gene SCARB1 which encodes HDL cholesterol receptor called scavenger receptor class BI (SR-BI) located on the liver cells, in 5 study participants. Among these 5 people, one person had 2 mutated copies of this variant gene.
Genetic manipulation of this variant gene in mice showed that increasing the level of HDL cholesterol had effects totally opposite to the expected ones. When the gene was overexpressed, it caused a reduction in the HDL cholesterol levels along with a decreased risk of atherosclerosis. If the gene was deleted, it resulted in increase in the level of HDL cholesterol with a simultaneous increase in the risk of atherosclerosis.
Genetic analysis of more than 300,000 people was done which showed that this variant called SCARB1 P376L, was linked to increased HDL cholesterol levels. People who carried this variant were found to have abnormally elevated blood levels of HDL cholesterol.
This prompted further research to look for the connection between SCARB1 P376L and the risk of heart diseases. The subsequent study included almost 50,000 people with coronary heart disease and about 88,000 controls. It was established that people who carried the variant gene had a significantly high risk of developing heart diseases.
Further experiments were carried out on the cell cultures and in mice which showed that P376L SR-BI protein was not processed by the cell the right way. Quite frequently, the protein could not reach the surface of the cell which caused the liver cells to lose their ability to take up the circulating HDL cholesterol.
This study has given valuable insight into the role of HDL cholesterol in the body. It showed that the function of HDL cholesterol within the body is more important than its concentration and helps determine whether it will prove to be beneficial or harmful for the heart.