In this edition:
Research from the Simcox Lab in the Department of Biochemistry uncovers new details about the relationship between cells regulating the breakdown of a lipid, cells’ energy expenditure, and metabolic disease. Here’s the run down on their latest research, published in Cell Metabolism:
- Under metabolic stress, our bodies break down energy stores to allow us to survive. The process is tightly regulated and primarily happens in a part of the cell called the lysosome.
- Dysregulation of lipids in the lysosome can result in metabolic disease such as cancer, diabetes, and neurodegenerative disorders.
- Researchers in the Simcox Lab identified an enzyme that helps to break down lipids that control energy expenditure.
What background information do you need to know?
When our bodies are under stress from, for example, nutrient deficiency or exposure to extreme cold, our cells break down stored energy in the form of lipids, a process that often occurs in an organelle in the cell known as the lysosome. One way cells access stored energy is by releasing enzymes that dock to BMP lipids, initiating the breakdown of other lipids in the lysosome. In times of stress, both BMP lipids and the enzymes that dock to them increase in abundance to break down more lipids. However, a dysregulated build-up of BMP lipids is associated with a variety of diseases, including diabetes and neurodegenerative disease, and can happen in exposure to extreme cold.
Why do BMP lipids sometimes build up, resulting in disease?
We don’t really know. Despite their vital importance, it’s been difficult to identify which enzymes are responsible for regulating BMP lipid levels through synthesis or breakdown. Identifying these enzymes, and how they are regulated, will provide key insights into potential to develop therapeutics for systems gone awry.
How have scientists made progress?
Scientists in the Simcox Lab have identified a liver enzyme in mice and humans that helps to break down BMP lipids, regulating their abundance in cells.
The researchers increased levels of BMP lipids in liver cells through cold exposure. The scientists identified the enzymes that are more abundant during this cold exposure and that were in the lysosomes where BMP lipids are localized. This led them to hypothesize that the regulatory protein Pla2g15 is responsible for breaking down BMP lipids. Their further experiments showed that in cells with functional Pla2g15 proteins, BMP lipids were broken down and decreased in abundance, while in cells with dysfunctional Pla2g15 proteins, BMP lipid levels remained elevated.
The researchers believe that Pla2g15 may play an important role in our survival during times of metabolic stress. In future research studies, they plan to explore the relationship between Pla2g15 dysfunction and metabolic diseases. In collaboration with researchers at Stanford University, additional research from the Simcox Lab has already shown that inhibiting Pla2g15 activity can lead to a greater abundance of BMP lipids, which can help to break down other accumulated lipids responsible for the symptoms caused by a neurodegenerative disorder.
Written by Renata Solan.
In Research In Brief: The What, Why, and How, we explore new research from the UW–Madison Department of Biochemistry to learn more about the world around us — and inside us.
This edition of Research in Brief: The What, Why, and How is based on the following publication: Davidson, Jain, et al. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycerol)phosphate lipids by phospholipase A2 group XV. Cell Metabolism, May 2025, 300(8):107544. This research was done in collaboration with the University of Michigan and Stanford University and was funded in part by the Glenn Foundation and American federation for Aging Research, the National Institutes of Health (NIH) and NIH National Institute of Diabetes and Digestive and Kidney Diseases, a Hatch Grant, and the Juvenile Diabetes Research Foundation. Judith Simcox is an HHMI Freeman Hrabowski scholar.