Protein Nrf1 prevents high cholesterol in cells

In a new study, researchers from Harvard's Chen Zengxi School of public health in the United States have elucidated a key molecule in cholesterol metabolism, which plays a role of molecular sentinel in cells and helps keep cholesterol levels within a safe narrow range The molecule, called Nrf1, detects and reacts to excess cholesterol It may represent a potential new therapeutic target for a variety of diseases with impaired cholesterol metabolism The relevant research results were published in the cell Journal on November 16, 2017, and the paper title was "Nrf1 is an ER membrane sensor that is central to cholesterol homestasis" The corresponding author of the paper is Professor g ö Khan s Hotamisligil, director of the center for nutrition, genetics and metabolism of Sabri janyuk, Chen Zengxi School of public health, Harvard For decades, it has been accepted that high blood cholesterol levels are the basis for cardiovascular disease and other major health problems But at the cellular level, elevated cholesterol levels are more dangerous, leading to toxicity, inflammation, and even cell death "Cells have to stop cholesterol rising - it can't tolerate too high or too low cholesterol levels," Hotamisligil said Although there are known cytokines that send and receive signals when cholesterol is in short supply (coordinated by a protein called SREBP2), it is not clear how cells deal with some of the crucial harmful aspects of cholesterol excess " To explore the mechanism of protecting cells from cholesterol accumulation, lead author Scott widenmaier and colleagues focused on the endoplasmic reticulum organelles in cells The endoplasmic reticulum is surrounded by a membrane with a particularly low cholesterol content (in fact, lower than any other cell membrane) "It's a particularly vulnerable place in the cell where a small increase in cholesterol levels can have a significant effect," Hotamisligil explains As an intracellular structure, endoplasmic reticulum needs to maintain its fluidity Adding more cholesterol to its membrane will make it more vulnerable Based on their hypothesis, the researchers set out to find molecules in the endoplasmic reticulum that may play a role in detecting or responding to cell cholesterol levels; they focused on several potential candidates In the initial experiment, Nrf1 protein stood out because it reacted to cholesterol - when cholesterol was added to cells, Nrf1 levels increased, indicating that the protein was able to respond to high cholesterol When Nrf1 function is destroyed in mice, the liver significantly expands and has excessive cholesterol, which suggests that it usually plays a role in protecting the liver from cholesterol accumulation In order to further study the protective effect of Nrf1 on cholesterol metabolism, these researchers set out to determine how it plays a role at the molecular level They found that Nrf1 was able to bind directly to cholesterol and identified specific regions in the protein that mediate this binding Moreover, this cholesterol binding triggers a chain of molecular events that inhibit inflammation and promote cholesterol removal from cells Hotamisligil said, "this discovery really teaches us a lot about how cells maintain cholesterol balance in the body Today, we confirm that a molecular yin-yang system formed by Nrf1 and SREBP2 keeps cholesterol levels in a safe, narrow range in cells This is an exciting finding and may have a wide range of new therapeutic applications "