Dolichols Vital to Cell Function

dr_duane_graveline_m.d._134By Duane Graveline, MD, MPH

Statins achieve their cholesterol lowering effect by inhibiting an enzyme in the liver responsible for cholesterol production. Along with this reduction in cholesterol, other essential metabolic functions are also affected.

The diagram on the Cause of Statin Side Efects page, - click this link: Causes of Statin Side Effects - illustrates the pathway where statins act and the many organic processes that are consequently disrupted. It also lists the side effects that are possible as a result of artificially limiting production of these fundamentally important elements. The biosynthesis of CoQ10 is one process that is inhibited by statin drugs—CoQ10 is essential for the production of energy in the body.

The dolichols are another area of collateral damage from statin use. This class of compounds is involved in an intricate process of cellular activity involving message transport, neuropeptide formation and mitochondrial DNA error correction.

Is it any wonder that doctors today are completely baffled by their statin damaged patients. Most have not the slightest idea of the chaos statins have caused in their patient's cell function. They are not alone. Nobody in the drug companies or the government regulatory bodies seem to understand it any better.

Proteins manufactured in response to DNA directives are packaged into transport vesicles that are shuttled across the cytoplasm to their various destinations. It is here that the vital process of glycosylation occurs.

Without dolichols there is intracellular chaos as various proteins cannot be directed to their proper target and are, in effect, dead-lettered. The post office analogy, though childishly simple, comes very close to describing dolichol's altered function when made deficient by statins.           

Neuropeptides are biochemicals that regulate almost all life processes on a cellular level, thereby linking all body systems. Although produced primarily in the brain, every tissue in the body produces and exchanges neuropeptides. Called messenger molecules, they send chemical messages in the form of linked peptides from the brain to receptor sites on cell membranes throughout the body. 

Not only do these protein chains carry information throughout the body, they mysteriously seem to be the information itself. They do not simply convey thought, sensation or emotion; these peptide clusters are the thought, sensation or emotion in a process we are only just beginning to understand. 

It is now suspected that the hundreds of cases of statin associated hostility, aggression, irritability, paranoia, homicidal ideation, depression and suicide are somehow linked to dolichols and altered cell messaging.

Another role of dolichols is in DNA error correction involving a class of glycoproteins known as glycohydrolases. A specific one of these is required for every DNA error. Daily our somatic and mitochondrial DNA files are searched and corrected. 

Tens of thousands of these errors occur daily and must be identified and repaired. Not too different from the spell checker in a computer word processor application. This is the job of glycoproteins and dolichols and the reason for the concern that statins inhibit dolichols.

Siddals work told us that diabetes was inevitable with statin use.(1) Siddals and others of the UK reported that, “statins disrupt cellular processes by the depletion of isoprenoids and dolichol. Insulin and insulin-like growth factor (IGF) signaling appear particularly prone to such disruption.”

Extending Siddal’s work on insulin growth factors, Robert Smith MD and his team working with colleagues in France and Italy have identified more than seven different forms of insulin growth factor-like mutations in their studies of Parkinsonism patients.(2) 

This work suggests that the specific effect of statin drugs on this signaling mechanism may be influencing Parkinsonism development as well, at least in some people. The entire process of glycoprotein synthesis is under the direction of our dolichols and diminished availability of dolichols is known to be associated with statin use.

These mutations in the GIGYF2 gene consisted of a single amino acid substitution in the protein encoding for this gene. This is the kind of defect that results from mistakes made in the placement of sugars during the process of glycoprotein formation. If the glycoprotein is faulty in its makeup, the genes it encodes will be defective and that is what Smith is reporting. Glycoprotein synthesis takes place in the endoplasmic reticulum of our cells. Think of them as mini-factories working assembly line fashion, for that is what they truly are.

In this study of Smith’s, colleagues in Milan, Italy and Paris, France provided close to 250 DNA samples from patients who had Parkinson’s and at least one first-degree relative (parent, child or sibling) with the disease. This included 123 Italian patients and 126 French patients. For comparison, they also studied DNA from more than 200 unrelated healthy controls from both countries. None of the mutations were observed in healthy controls.

The vast majority of DNA damage affects the DNA bases themselves with a single amino acid substitution in the protein of the nucleotide base. In the repair process this damaged DNA base must be excised and removed completely, requiring a specific glycohydrolase enzyme and it must be replaced with the correct nucleotide (occurring with some unbelievable frequency daily in every cell in the body!)

It boggles my mind to think of the complexity of this micro-processing and the incredible gall of the pharmaceutical industry to think they could get away with dolichol inhibition. It was bad enough they assumed our bodies would not be affected by CoQ10 deprivation. As vital as CoQ10 is to cell function the role of dolichol role is even more complex. Obviously, we are only just beginning to understand it. We are still years away from complete understanding.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor 

References
1. www.jbc.org/content/279/37/38353.full
2. www.ncbi.nlm.nih.gov/pmc/articles/PMC2427211/

February 2015
 


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