The first speaker on the Age-Related diseases Track at RB2015 is Jay Jerome, Associate Professor of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine. In his talk titled Lysosomes, Lipids and Longevity he focused on cholesterol with respect to lysosome function, specifically in macrophages. Why cholesterol? It’s related to diseases of aging and specific to cardiovascular disease.
Looking for Lipids
For some background, the lysosome is a digestive organelle that breaks down components so a cell can remove unwanted or hazardous material, or resynthesizes it for cell usage. So these hungry little digesting machines are key homeostatic organelles, and when they go awry, disease states can happen. While we know how disease states occur due to pathogens and injury, we know little about how they are brought about due to slow, toxic damage over a long period of time. And these long-term chronic killers can certainly pose an impediment to quality lifespan. Given that cardiac disease is the number one killer in the USA, exploring the lipid profile in atherosclerosis is a crucial way to make some real progress in understanding the aging pathway that leads to the massive problem of heart disease.
Apparently, we all have atherosclerosis. Atherosclerosis is simply the slow, steady increase in artery wall thickness (or conversely a slow decrease in lumen, the space where the blood flows). Think of it like your bathroom pipes. After so many years, the gunk in the pipes can build up and may even cause a clogging problem. But the question is not whether you have it (we all do), but how fast it progresses. And this is where cholesterol comes in. Cholesterol is critical for health, forming a key component of cellular membranes by making them less fluid and thus less leaky. These plasma membranes along with lysosomes have a particular concentration of cholesterol. And without sufficient cholesterol, our cells die and then we die. But too much is also toxic. How do we find the balance to exploit it for enhancing the health span of our cells?
The Cholesterol Trap
There are two reasons for lysosomal cholesterol accumulation: 1) the oxidation of the cholesterol molecule (LDL) whereby oxysterols inhibit lysosomal enzymes, create leaky membranes and increase cell death. And 2) cholesterol inhibition of lysosome pH. Lysosomal enzymes require acid (low) pH. So in a series of studies designed to understand how to clear the excess cholesterol from the lysosomes, his lab grew macrophages in a dish and incubated them with lipids and to see what happened. In the cell, free cholesterol must partition into membrane and then pinch off to the extracellular space. Proton pumps work to keep the environment acidic but when the free cholesterol doesn’t pinch off, pH goes up and enzymes quit working. Hello clogged arteries. Is there a way to clear the stuff out? What if they load up the cell with aggregated LDL and then chased it by treating with triglycerides? They tried this and saw a significant decrease of cholesterol in the cell. But how are triglycerides affecting cholesterol metabolism? Since macrophages have lipases on surface, could inhibiting the surface lipase make a difference? Using Orlistat, an inhibitor of lipase did not work. What about inhibiting the process of endocytosis? Monodansylcadaverine (yes, like cadaver) could inhibit endocytosis by 30%. After three days of VLDL treatment they saw a dramatically reduced ability of TG to clear the cholesterol out of cells with this compound – so it turns out the pathway is in endocytosis.