Project 452283

The liver is responsible for managing lipids, mostly cholesterol and triglycerides. It does so by absorbing them from the blood when they are in excess and releasing them in circulation when they are not enough, such as after a rich meal and during fasting, respectively. Three cellular organelles manage the uptake, release, and elimination of these lipids: the mitochondrion, the endoplasmic reticulum (ER), and the peroxisome. Because the liver must handle a large quantity of lipids, its cells contain hundreds of copies of each of these organelles. However, we recently discovered that, unlike other cell types, in the liver cell these organelles are bundled together into many "3-organelle tokens", each "token" consisting of 1 ER + 1 mitochondrion + 1 peroxisome. The "raison d'être" of such unique spatial and structural organization of the liver cell is not known. So, this research project aims to discover what bundles the organelles together into "tokens" and what happens to the liver without them or with too many of them. This is critically urgent and important to discover because the major consequence of obesity, alcoholism, and Type-2 diabetes is that of crashing the liver's ability to handle lipids and trigger liver inflammation, cancer and necrosis. Therefore, by learning how to increase or decrease the "3-organelle tokens" in the liver cell, new therapies can be designed to prevent liver failure and cancer in obese, alcoholic and diabetic patients.