Obesity and its related ailments like type 2 diabetes and fatty liver disease pose a major global health burden, but researchers report in Nature Communications that blocking an RNA-silencing protein in the livers of mice keeps the animals from getting fat and diabetic conditions.
Takahisa Nakamura, and colleagues at Cincinnati Children’s Hospital Medical Center genetically deleted a protein called Argonaute 2 (Ago2) from the livers of mice. Ago2 controls the silencing of RNA in cells, affecting energy metabolism in the body, according to the study. When Ago2 silences RNA in the liver, it slows metabolism and liver’s ability to process a high-fat diet, the scientists report.
When they deleted Ago2 from the livers of mice, it was not toxic to the animals but it did stabilize energy metabolism. This helped stave off obesity and prevented the mice from developing diabetes and fatty liver disease, which can severely damage the vital organ–which helps rid the body of toxic substances.
“Although this is still basic science, we propose that there may be important translational implications for our findings for chronic metabolic disorders like diabetes, fatty liver diseases, and other obesity associated illnesses,” said Nakamura, senior investigator and a member of the Division of Endocrinology. “This allows us to explore the potential of finding a novel therapeutic approach that alters energy balance in obesity and modulates the associated diseases.”
The scientists caution the research is early stage. Their findings still need additional study and verification in laboratory models and the development of a practical therapeutic to inhibit Ago2 in a clinical setting for patients. But the current paper provides a solid basis for subsequent work.
Ago2 was identified after the researchers conducted a thorough screen and analysis of the activity of genes and their molecular targets in the liver, such as critical proteins. They analyzed wild type and genetically modified mice with high-fat diets by deleting certain proteins that are critical to liver metabolism–such as one called AMPK (AMP-activated protein kinase).
Nakamura said that identifying Ago2’s role in the process “connects the dots” between how proteins are translated in the liver, how energy is produced and consumed and the activity of AMPK in these processes. He pointed out that disruption of these events is already a common feature in obesity and its related illnesses.
Seung-Hoi Koo discusses his recent article in Nature Communications: Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
More information can be found on the website of Professor Seung-Hoi Koo: https://koreauniv.pure.elsevier.com/en/persons/seung-hoi-koo
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, narrow range. Known as Nrf1, it both senses and responds to excess cholesterol, and could represent a potential new therapeutic target in a multitude of diseases where cholesterol metabolism is disrupted.
“We’ve uncovered a key missing piece in our understanding of how cells can precisely control their cholesterol levels,” said senior author Gökhan S. Hotamisligil, J.S. Simmons Professor of Genetics and Metabolism and head of the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research at Harvard Chan School. “That piece forms part of a molecular yin-yang that is critical for keeping cholesterol levels in proper balance and ensuring proper cellular function.”
It has been accepted for decades that high cholesterol in the blood can set the stage for cardiovascular disease and other significant health problems. But elevated cholesterol is even more dangerous at the cellular level, leading to toxicity, inflammation, and eventually cell death. “The cell must guard against any rise in cholesterol — it cannot tolerate levels that are too high or too low,” said Hotamisligil. While there are well known cellular factors that send and receive signals when cholesterol is in short supply (orchestrated by a protein called SREBP2), it has been unclear how cells handle some crucial aspects of the converse problem of too much cholesterol.
— Dr Mandy Drake (@TeamDrakeUofE) November 17, 2017
To explore the mechanisms that defend cells against cholesterol, first author Scott Widenmaier, research fellow in the Department of Genetic and Complex Diseases and Sabri Ülker Center, and colleagues focused their attention on an area of the cell known as the endoplasmic reticulum or ER, which is surrounded by a membrane notoriously low in cholesterol — lower, in fact, than any other cellular membrane. “This would be a particularly vulnerable place in the cell, where a small increase in cholesterol would make a significant impact,” explained Hotamisligil. As an intracellular structure, the ER requires fluidity, and adding more cholesterol to its membrane makes it more brittle.
Based on their assumption, the scientists set out to find molecules that reside in the ER membrane and that might play a role in detecting or responding to cellular cholesterol levels; they homed in on a handful of likely suspects. In initial experiments, Nrf1 protein stood out because it responds to cholesterol — when cholesterol is added to cells, the levels of Nrf1 increase, indicating that the protein can react to high cholesterol. And when Nrf1 function is disrupted in mice, the liver becomes dramatically enlarged and overrun with excess cholesterol, suggesting that it normally acts to protect the liver from cholesterol accumulation.
To dig more deeply into Nrf1’s protective role in cholesterol metabolism, the researchers set out to determine how it works at the molecular level. They discovered that Nrf1 has the capacity to bind to cholesterol directly, and pinpointed specific regions of the protein that mediate this binding. Moreover, the binding of cholesterol triggers a cascade of molecular events that suppress inflammation and promote cholesterol removal from the cell.
Taken together, these findings highlight a novel program for responding to high cholesterol in the cell that operates alongside other molecular components that guard against low cholesterol.
“This discovery really teaches us a lot about how cells maintain cholesterol homeostasis,” said Hotamisligil. “Now, we demonstrate that there is a molecular yin-yang– formed by NRF1 and SREBP2 — that together keep cellular cholesterol within a safe, narrow range. That’s an exciting finding that could have broad, new therapeutic applications.”
Research article: NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis