The ER and Metabolic Guardians of Metabolic Biology

The ER is a central organelle for protein synthesis and protein folding in the cell, and as such, is key to the maintenance of cellular homeostasis. ER proteins including chaperones, oxidoreductases, and glycosylating enzymes direct proper folding, modification, and assembly of newly synthesized polypeptides before they are directed to secretory pathways. Despite this active machinery, the error-prone nature of the folding process results in misfolding of up to one-third of nascent polypeptides. These improper forms of proteins are recognized and disposed of by robust quality-control systems such as ER-associated degradation, removing misfolded peptides to the cytosol for ubiquitylation and degradation by the proteasome.

Studies in our lab demonstrated the metabolic biology of the ER and how this organelle adapts, or fails to do so, under specialized and extreme challenges, particularly in key metabolic organs. This interest has recently led us to the discovery of the role of Nrf1 (also known as Nfe2L1) in two circumstances where the canonical Unfolded Protein Response (UPR) is 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 belongs to a family of four related transcription factors and is a ubiquitously expressed ER-membrane spanning protein, belonging to the Cap’N’Collar (CNC) family of transcription factors involved in stress adaptation and detoxification. 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.  In the absence of hepatic Nrf1, liver succumbs to massive cholesterol toxicity.  Whereas in brown adipose tissue, Nrf1 regulates proteasome activity during cold exposure to maintain the functional integrity of this tissue, offering a key role for regulated proteasome activity in metabolic homeostasis.

So far, our studies have shown that Nrf1 has a role in guarding homeostasis through various mechanisms in the liver and brown adipose tissue, and thus could be utilized under pathological conditions to restore health of organs. We are incredibly excited for the potential of this protein to create novel therapeutic avenues to treat liver diseases and other disorders with underlying ER maladaptation. In particular, we are actively investigating the molecular mechanisms of Nrf1 action in metabolic adaptation in health and how such activity can be exploited for therapeutic strategies against immunometabolic diseases.

Suggested Readings:

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004 Oct 15;306(5695):457-61. doi: 10.1126/science.1103160. Abstract

Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, Saksi J, Bartelt A, Hotamisligil GS. NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis. Cell. 2017 Nov 16;171(5):1094-1109.e15. doi: 10.1016/j.cell.2017.10.003. Abstract

Bartelt A, Widenmeier SB, Schlein C, Johann K, Goncalves RLS, Eguchi K, Fischer AW, Parlakgul G, Snyder NA, Nguyen TB, Bruns OT, Franke D, Bawendi MG, Lynes MD, Leiria LO, Tseng YH, Inouye KE, Arruda AP, Hotamışlıgil GS. Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasome activity. Nature Medicine. 2018 Mar; DOI: 10.1038/nm.4481. Abstract