Seeking to Further Understand the Role of Cholesterol Sensor NRF1

Despite the development of effective strategies for lowering cholesterol, atherosclerosis and associated cardiovascular diseases remain a major global health burden. Work in recent years has highlighted the exciting therapeutic potential for interventions that reduce inflammation, as well as the need for identifying novel and selective targets. The Sabri Ülker Center is focused on understanding how lipid metabolism and inflammation interact, and how these interactions can be useful therapeutically. In our earlier work, we discovered Nrf1 protein as a novel cholesterol sensor to defend against cholesterol toxicity and inflammatory damage. The central premise of this project is that Nrf1 in the macrophage is a critical factor for preventing chronic inflammation and maintaining cholesterol homeostasis, and that enhancing these actions of Nrf1 may be beneficial in atherosclerosis with implications for other immunometabolic diseases.

We believe that our research will determine the role of Nrf1 in the regulation of inflammation, specifically investigating the importance of Nrf1 function for controlling inflammatory responses of the macrophages, an immune cell type that plays a very critical role in the development of atherosclerosis.

In ongoing studies, we have obtained substantial new knowledge about the role and action of macrophage Nrf1, in terms of underlying mechanisms of action and impact on macrophage phenotypes. To follow up on the effect of macrophage Nrf1 deficiency in the context of early and advanced atherosclerosis, we have completed studies in multiple cohorts of genetically modified mouse models of atherosclerosis and deficiency of Nrf1 in specific cells, to demonstrate the critical role of this pathway on disease development. We are also examining the organs of these animals to study cholesterol-induced inflammation and cell death which can be modulated by Nrf1. Our studies, so far, support the intriguing possibility of an involvement of Nrf1 in the crosstalk between cholesterol metabolism and inflammation. In addition to the Nrf1-deficiency models, we have also completed the development of both a genetic mouse model and virus-mediated gene transfer methodology, to test the therapeutic profile of increasing Nrf1 activity in the desired cell types and tissues. This critical milestone is an important development for our translational studies, particularly against liver and heart diseases. We are excited for embarking on these new avenues with the goal of generating new therapeutic possibilities against multiple debilitating and common immunometabolic diseases.

We are grateful to the National Institutes of Health USA and Servier Research Foundation for providing funding and logistic support for these projects.

“The Nrf1 team includes Dr. Isabel Graupera, Dr. Shijun Deng, Jessica Freed, Alanis Carmona, and Dr. Zhe Cao, who focus on new mechanisms of metabolic defense by Nrf1 and how it can be used to treat deadly metabolic diseases. We discovered the role of Nrf1 in two circumstances where the previously known adaptive mechanisms were insufficient, or even dispensable, to account for the adaptation to metabolic stresses specifically in the liver, upon cholesterol overload and in brown adipose tissue upon cold exposure. Nrf1 can sense cholesterol levels in the ER membrane through its direct binding to cholesterol and mount a defensive program to protect the liver tissue. Our studies have shown that Nrf1 has a role in guarding homeostasis through various mechanisms and thus, could be utilized under pathological conditions to restore the health of organs. We are incredibly excited about our ongoing efforts and for the potential of this protein to create novel therapeutic avenues to treat liver diseases and other disorders with underlying organelle maladaptation.”

Gökhan S. Hotamışlıgil, MD, PhD