Today was TRASH DAY in my neighborhood, and occasionally I wind up outside at the precise moment that the Garbage Man arrives to dispose of our weekly waste.

And when I meet someone for the first time, it’s nice to find some common ground to “break the proverbial ice,” so the fact that I had just read THIS ARTICLE seemed particularly serendipitous!  Since it discussed the role of cholesterol in the lysosome, which is the cellular Garbage Disposal, I figured that this Garbage Man would be eager to “chemically bond” over some light-hearted Lipid Banter.

Well, our trash can is still full, but hopefully you’ll stick around and listen to me Brain Dump my thoughts on this publication before you drive away!

So this article discussed the role of cholesterol in MITOPHAGY, which is when the lysosome disposes of damaged mitochondria.  This is a type of autophagy, which I previously discussed in THIS POST as “Cellular Housekeeping.”  Here are the key takeaways:

1. When mitochondria are damaged and MITOPHAGY is necessary, the cholesterol content in lysosomal membranes INCREASES.  Logically, enzymes related to cholesterol synthesis (HMGCR) and cholesterol uptake (LDLR) are increased along with oxysterol-binding protein (OSBP) to transport the cholesterol to the Recycling Station.
   1. This cholesterol accumulation is also correlated with increased levels of PI4P, which probably doesn’t do much for you…however, this phosphatidylinositol isoform would be negatively regulated by INSULIN, as insulin, an “anti-autophagy” signal, would generally coordinate PI3K-Akt signaling.  Insulin would be upregulated by eating, whereas fasting would downregulate insulin and upregulate PI4P.  You get one more piece of PIE (4 vs 3) when you haven’t eaten, ironically!
2. When cholesterol is experimentally depleted in the lysosome (via a statin, for instance), mitophagy is inefficient, the lysosome displays increased fragility, and the normally acidic lysosomal pH becomes more alkaline.  Essentially, your Garbage Bin is more likely to crack and the Garbage Disposal is more likely to leave its contents un-mulched.
   1. Part of the way that cholesterol optimizes lysosomal pH is via the assembly of vacuolar ATPase…since we’re on the topic of Housekeeping, you can remember this V-ATPase as a “Vacuum” assisting in overall autophagic processes.

Now if one of the Cholesterol Conspiracy people cherry-picks this study as evidence that any cholesterol-modulating medication will kill you and that “optimal” blood cholesterol levels are “as high as possible,” consider this:

1. There is a big difference between PLASMA CHOLESTEROL and CHOLESTEROL IN CELL MEMBRANES/OTHER TISSUES
   1. Every nucleated cell in your body synthesizes its own cholesterol, since a lack of cholesterol is incompatible with life.
2. The cells used in this study were HUMAN KERATINOCYTES.
   1. I’ve got no “skin in the game” here (that was terrible), so hopefully that inspires some trust. Despite what you may have heard at the nail salon or Med Spa, keratinocytes may not be the most important cell type to employ when you’re trying to make generalizations about, say, cholesterol regulation in the brain, for instance.  Because yes, some of the earliest problems that we observe in people who go on to develop Alzheimer’s Disease are impaired lysosomal function and toxic lipid droplet accumulation.  However, it does highlight the “Sweet Spot” of cholesterol in physiology.  Too much, and we see massive problems, but too little, and the cell is unviable.  In fact, we see massive luminal lysosomal cholesterol accumulation in horrible neurodegenerative diseases like Niemann-Pick C Disease, further reinforcing the importance of Cholesterol Homeostasis.

So anyway, hopefully the Garbage Man comes back later to dispose of our trash, and hopefully your lysosomal Garbage Disposals are thriving as well.  Control your insulin, control your life…and I bet that your mitophagy will be well-controlled, too!