Scientists from the National Institutes of Health (NIH) and Johns Hopkins Medicine worked together to analyze human and mouse epigenomes and discovered that drinking alcohol could lead to epigenetic changes that influence a particular gene’s ability to regulate cholesterol. The results suggest an underlying epigenetic mechanism known as DNA methylation could explain why someone’s body processes cholesterol differently depending on their drinking habits. It also offers unique insight into the effects of cholesterol-lowering drugs which are commonly used to reduce LCL cholesterol, or bad cholesterol.
The gene known as PCSK9 functions to make a protein which regulates the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance created in the body and found in animal-product foods. According to the NIH, your blood cholesterol level has a lot to do with your chances of getting heart disease. The higher the level, the more at risk a person is for poor health.
Overall, the study’s findings hint that epigenetic changes to PCSK9 are linked to alcohol consumption and vary depending on how much someone consumes. The researchers, who published their study in Molecular Psychiatry, indicated that their evidence only points to an association and not necessarily cause-and-effect. Additional studies are needed to demonstrate a direct link, if one does exist.
“Small amounts of alcohol are well known to be seemingly protective against heart disease in some studies, whereas heavy, chronic alcohol use can have detrimental effects on the liver as well as on the cardiovascular system,” said Zachary Kaminsky, Ph.D., Assistant Professor of Psychiatry and Behavioral Sciences. “Regulation of PCSK9 seems to correlate with this pattern and may be a significant underlying factor behind the variations in the relationship between cholesterol and cardiovascular disease when it comes to alcohol use.”
Epigenomics is a powerful new way of studying the adjustments in gene expression, caused by the environment or other factors, that do not change the DNA itself.
The group measured how alcohol consumption could lead to epigenetic changes, or whether genes were turned “on” or “off”. They investigated DNA “chips”, also known as microarrays, which revealed the genes that had attached methyl marks, a chemical group referred to as CH3. Around 450,000 methyl groups were assessed at a time.
DNA methylation influences the level of gene expression by repressing transcription and thereby reducing the expression of particular genes. Methylation has been one of the most widely studied marks as researchers add to the growing body of work on the relatively new field of epigenetics.
Several sets of data were utilized by the team. One set included DNA extracted from brains of individuals who had alcohol abuse or dependence and had passed away. They compared these samples to the samples of 23 healthy individuals whose DNA was collected at The University of Sydney, Australia.
An additional set of data compared DNA isolated from blood of 68 people who were dependent on alcohol to 72 healthy people recruited by the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA).
The final set of data pulled DNA samples from brains of 29 humans who suffered from major depression and compared them to the methylation levels to 29 non-depressed controls, some of whom were recorded as abusing alcohol.
The researchers delved into the epigenetic results from all data sets to investigate which epigenetic changes were present in all of them and which were not. They all shared in common DNA methylation levels on the gene PCSK9. The higher the levels of DNA methylation at the PCSK9 gene, they found, the greater the level of PCSK9 in the blood.
In other experiments, mice were fed alcohol for 10 days accompanied by single-binge feeding often seen in humans with alcohol use disorder, and looked at their epigenetic methylation profiles compared to mice that did not consume alcohol.
Then they took samples from the blood, liver, and brain and analyzed DNA for methyl marks on the PCSK9 gene and PCSK9 protein levels in the liver. For mice that were fed alcohol, the levels of methylation at the PCSK9 gene was boosted in all tissues they assessed. However, the mice administered alcohol had lower PCSK9 protein levels in their liver.
According to Kaminsky, the liver sample results were initially puzzling to the team. The liver tissue had more methyl groups, which typically suppress genes, but there wasn’t a corresponding increase in protein levels that would be expected. After looking further at human livers from those with a dependence on alcohol and those who had undergone a liver transplant, they found a similar pattern. There was an unusually low amount of PCSK9 proteins when there was a greater amount of methylation on PCSK9. It was actually only a third of the level of protein found in individuals who had no alcohol abuse.
However, they ultimately solved the conundrum. “Given that alcohol is metabolized by the liver and can cause liver damage if used in large amounts over long periods of time, this result made immediate sense,” said Falk Lohoff, M.D., of the NIAAA and the lead author. “The liver cells were dying, which is why we didn’t see the high levels of PCSK9 protein as would be expected.” They were able to confirm this by taking a look at patient tissue samples from those who had end-stage liver disease.
The regulation of PCSK9 by alcohol appears to be dynamic, according to Kaminsky and Lohoff, suggesting that little amounts of alcohol leads to reduced PCSK9 methylation and the expression of the cholesterol-related gene, whereas heavy, chronic alcohol use tends to lead to an increase in methylation of PCSK9 and increased gene expression, but ultimately lower levels of PCSK9 protein because of liver damage and dying liver cells.
This particular protein binds to the receptors for bad cholesterol and prevents the uptake and breakdown of it. This leads to an accumulation of cholesterol in the blood stream which can eventually clog the arteries. According to the CDC, 73.5 million adults in the US have high LDL, or bad cholesterol. Plus, those with high total cholesterol levels have nearly twice the risk for heart diseases compared to people with normal levels.
Recently, due to some individuals not being able to tolerate statins, people are using a novel class of drugs designed to reduce cholesterol. They work to reduce PCSK9 protein levels and remove the bad cholesterol from the bloodstream. However, these particular drugs carry some side effects and are expensive.
“So far, the safety and interaction of PCSK9 inhibitors and alcohol use hasn’t been studied, but this is an important area of research given how common alcohol use is,” said Lohoff. “Our finding of a PCSK9-alcohol link is intriguing, since PCSK9 inhibitors might be particularly useful in lowering bad cholesterol for people who have high PCSK9 levels due to drinking.”
He also indicated that inhibitors of PCSK9 aren’t metabolized by the liver, which often suffers damage from those drinking excessively. This would mean these PCSK9 inhibitors wouldn’t add additional strain to the liver as some alternative medicines could.
The group of researchers make note of their study’s limitations, especially because they investigated DNA from tissue samples at just a single point in time. Because of this, they cannot conclude whether the adjustments in epigenetic marks are stable for long periods of time or reversible.
Additional research will bring to light the nuances of the epigenetic mechanisms underlying alcohol consumption and how the body handles bad cholesterol, potentially increasing one’s risk of developing heart disease and other illnesses.
Source: Lohoff, F.W. et al. (2017). Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder, Molecular Psychiatry, 00, 1-11.
Reference: Johns Hopkins Medicine. Alcohol Use Affects Levels of Cholesterol Regulator through Epigenetics. News and Publications. 20 Sep 2017. Web.
