MedicalResearch.com Interview with:
Gokhan S. Hotamisligil MD PhD
J.S. Simmons Professor of Genetics and Metabolism
Chair, Department of Genetics and Complex Diseases
Department of Genetics and Complex Diseases
Department of Nutrition
Harvard Stem Cell Institute
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Cholesterol is often considered a ‘bad’ nutrient, as it has been strongly linked to a cluster of metabolic diseases. In reality however, cholesterol is absolutely vital for the health of all animal cells, serves as an essential building block for all membranes and precursor for essential molecules. It usually only becomes toxic when cells are exposed to high levels or free forms of cholesterol or when it is stored in excess.
The reasons why cholesterol over-accumulates or causes excessive damage in cells of some people is not entirely clear, as cells are normally should be able to remove such excesses, and there remains key mechanistic gaps in our understanding of how cells control the molecular process of sensing excess cholesterol, engage ways of removal and launch countermeasures to defend their integrity. Filling this gap may reveal a new path toward alleviating the burden of cholesterol-related diseases.
To this end, we identified a new signal pathway mediated by a protein called Nrf1, which enables cells to know when to remove cholesterol, thereby preventing excess cholesterol storage. We show that Nrf1 directly senses cholesterol in a strategic subcellular compartment called the endoplasmic reticulum and coordinates an adaptive and defensive responses that protects the cells and promotes the removal of cellular cholesterol.
MedicalResearch.com: What should clinicians and patients take away from your report?
Response: Cells are equipped with an intrinsic molecular cholesterol sensor called Nrf1 that coordinates adaptive changes in cellular behavior to alleviate the damaging effects and metabolic burden of excess cholesterol. Proper functioning of this adaptive system is central for cholesterol homeostasis. Similarly, finding ways to enhance this adaptive system might be an extremely promising therapeutic strategy against many diseases.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: In this study we showed a role for Nrf1 in preventing cholesterol build-up in liver, which was protective against liver disease. Future research should aim to delineate the underlying mechanism of action, whether this function of Nrf1 is protective in tissues related to other cholesterol-linked diseases such as atherosclerosis and neurotoxicity, and whether such actions of Nrf1 can be targeted or harnessed as a therapy. We are also curious to test whether Nrf1 is a broad metabolic guardian and may have other unique functions to protect the cells against metabolic stress and disease.
Disclosures: This study was supported in part by a grant from Servier Research Laboratories.
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NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis
Widenmaier, Scott B. et al.
Cell , Volume 171 , Issue 5 , 1094 – 1109.e15
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