Lessons from our Pupils: A Reflection [Podcast Episode 152]
Hello, Listeners! For this week’s blog post, we thought that we would take a closer look at Episode 152 (LINK) and bring you back to your experiences in the biochemistry classroom. In Episode 152 of the podcast, Jay spoke with Dr. Daniel Chao and Dr. Shriji Patel about a few “journal club” topics; one of these discussed a recent article published in JAMA Ophthalmology (LINK) about the possible role of statins in decreasing risk of diabetic retinopathy. With their proven mortality benefits related to cardiovascular disease, it is tough to go through a day in clinic without encountering at least one patient currently taking a statin. That being so, let’s go over how they work!
Statins are a class of lipid-lowering medications that act as competitive HMG-CoA reductase inhibitors. As you recall, this means that the statin binds to the active site of the HMG-CoA reductase enzyme and thereby limits its function. HMG-CoA reductase is utilized in one of the first steps (the rate-limiting step, in fact) of the mevalonate pathway, which converts acetyl-CoA and acetoacetyl-CoA into Cholesterol (see image below). As a result, less cholesterol is synthesized by the liver.
Image Credit: https://en.wikipedia.org/wiki/File:HMG-CoA_reductase_pathway.svg
However, this is not where the story ends. Statins also work to increase LDL (often referred to as “bad cholesterol”) uptake. The liver extracts cholesterol from the circulation through the use of LDL receptors, which sense and take up circulating LDL. Once statins inhibit the mevalonate pathway, the liver is able to sense the resultant decrease in cholesterol synthesis and up-regulates its LDL receptors. Once in the liver, the uptaken LDL can be processed into bile salts and other products, and there is less LDL floating in circulation.
The mevalonate pathway also includes the synthesis of prenylated proteins (“prenylated” refers to the addition of a hydrophobic lipid group to a molecule). It has been hypothesized that statin-related inhibition of these syntheses is related to some of the important cardiovascular benefits of the medication, including improved endothelial and immune cell function. The evidence for this idea is founded partially in the fact that other classes of drugs that reduce LDL levels—but do not affect prenylated protein synthesis—do not show these additional benefits. However, the effect on these proteins has also been hypothesized as a cause for unwanted side effects of statins, including myopathies and elevated blood glucose.
Back to ophthalmology, it reasonable to wonder whether the benefits found against diabetic retinopathy are related to these “other” cardiovascular effects, like improved endothelial function and modulated inflammatory responses. Although the results are debated, the JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin) study, for example, found that statins can have cardiovascular benefit in patients independent of LDL levels (in patients with already-low levels of cholesterol) through reductions in C-reactive protein levels. Time will tell as to what the role of statins will be in diabetic retinopathy, but it is interesting to consider yet another possible role this class of drugs may play.
-Michael Venincasa
For more information, check out: https://en.wikipedia.org/wiki/Statin