An organelle in our cells, called the endoplasmic reticulum (ER), plays an important role beyond the protein processing it is known for. It also senses and responds to internal and external immunological cues, as well as metabolic cues. One way to envision this structure is as a versatile and powerful cellular surveillance system.
That was the message brought by Gokhan Hotamisligil, M.D., Ph.D., from the Harvard T.H. Chan School of Public Health, as he delivered the 32nd Hans L. Falk Memorial Lecture.
He described lipids produced in our bodies as a prominent class of molecules sensed by the ER. Hotamisligil focused on cholesterol to illustrate the detection capacity and immunometabolic functions of this organelle.
“If a threshold of free cholesterol is achieved in the cell, it can be catastrophic,” he explained. Hotamisligil showed that the role of the ER in sensing cholesterol seems to be fundamental for keeping levels of this lipid normal, preventing inflammation and damage, and preserving liver function.
Sensing and responding to metabolic alterations
“Sensing our metabolism is fundamental for health, because alterations in one metabolic pathway or organelle can have profound consequences to cells and the whole body physiology,” said co-host Xiaoling Li, Ph.D., who leads the NIEHS Metabolism, Genes, and Environment Group.
Hotamisligil suggested that alterations in the ER can directly affect the ability of cells to produce energy, because of the organelle’s effects on mitochondria, the power house of cells. The organelles are known to be in physical contact with one another. They exchange signals and share some metabolic functions, including handling intracellular calcium.
Integrated metabolism and inflammation
Hotamisligil showed that impairment in the sensing ability of the ER leads to alterations in many cellular pathways, including those involved in immunity. He said that the ER works as an immunometabolic hub in our cells.
“His research has been fundamental to understanding that alterations in metabolism lead to activation of a chronic and low-grade inflammation, which exists in many human diseases, such as obesity, diabetes, and atherosclerosis,” said Anton Jetten, Ph.D., the other co-host, and head of the NIEHS Cell Biology Group. The state of chronic low-grade inflammation is called metaflammation.
In the case of obesity, this metaflammation leads to an increased risk for development of secondary complications and other diseases. “The new pathways Gokhan has characterized could be used to develop new drugs,” Jetten said.
Research published by Hotamisligil’s group demonstrated that using immunometabolism as target for new drugs could become an effective strategy to treat low-grade chronic inflammation associated with complex human diseases.
Possible impact of the environment
Falk was an avid advocate for research to understand the influence of the environment in human diseases. Scientists at NIEHS, including NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D., were interested in Hotamisligil’s plans for future research regarding the effects of different environmental factors.
As Hotamisligil explained, “The endoplasmic reticulum is a sensor for multiple signals, such as nutrients and lipids, as well as toxins, environmental pollutants, drugs, chemicals and xenobiotics.” New research in this area might be of fundamental importance to understanding the role of the environment in complex human diseases.
(Douglas Ganini da Silva, Ph.D., is a research fellow in the NIEHS Free Radical Metabolism Group)
Hotamisligil GS. 2017. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47(3):406–420.
Hotamisligil GS. 2017. Inflammation, metaflammation and immunometabolic disorders. Nature 542(7640):177–185.