Contact Information

Office: 1-570 BSB 
Phone: 319-335-7739 
Faculty Profile

Brief description of current research:

Our long-term goal is to understand how cells adapt to chronic stress, and to identify how these changes broadly influence cellular and organismal physiology. The endoplasmic reticulum (ER) is the site of synthesis and folding of secretory and cell-surface proteins. The cellular response to ER stress (also known as the Unfolded Protein Response, or UPR) serves as a model for understanding not only the mechanisms by which stress is sensed, but also the ways in which the consequences of alterations to homeostasis in one location (i.e., the ER) impact diverse areas of cell function. We have uncovered exciting evidence that perturbation in the ER disrupts lipid metabolism in the liver, leading to fat accumulation (steatosis). This connection has implications for both normal physiology and disease. We have found that inhibition of fatty acid beta-oxidation by the UPR protects ER function, and are currently pursuing the hypothesis that UPR activation during fasting/feeding cycles contributes to normal homeostatic regulation of lipid metabolism. We have also found that the ER stress-regulated transcription factor CHOP directly suppresses metabolic gene expression, and also that CHOP contributes to inflammation, fibrosis, and hepatic oncogenesis in both mice and humans. Our major goals moving forward are to understand the role played by ER stress and UPR signaling in obesity-linked fatty liver, and also the mechanisms by which CHOP promotes inflammation and hepatocellular carcinoma.

3 most influential diabetes/obesity/metabolism publications:

• Tyra HT, Spitz DR, and Rutkowski DT. Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress. Molecular Biology of the Cell 23, 811-819 (2012).
• Chikka MR, DeZwaan McCabe D, Tyra HM, and Rutkowski DT. C/EBP Homologous Protein (CHOP) contributes to suppression of metabolic genes during ER stress in the liver. Journal of Biological Chemistry 288, 4405-4415 (2013).
• DeZwaan-McCabe D, Sheldon RD, Gorecki MC, Guo DF, Gansemer ER, Kaufman RJ, Rahmouni K, Gillum MP, Taylor EB, Teesch LM, and Rutkowski DT. ER stress inhibits liver fatty acid oxidation while unmitigated stress leads to anorexia-induced lipolysis and both liver and kidney steatosis. Cell Reports 19, 1794-1806 (2017).

Quote:

“Studying stress responses has taught me that the farther we get from homeostasis, the harder it is to get back. Small changes to lifestyle now prevent having to make large changes later in life.”