Walter Klimecki

Walter Klimecki

Associate Professor, Veterinary Medicine
Assistant Professor, Medicine - (Research Scholar Track)
Associate Professor, Pharmacology and Toxicology
Associate Professor, Public Health
Associate Professor, Genetics - GIDP
Adjunct Associate Professor, Nursing
Associate Professor, BIO5 Institute
Contact
(520) 626-7470

Work Summary

Walter Klimecki's research program involves the balance between the particular DNA sequence “versions” of genes that we inherit from our ancestors, and the particular environmental exposures that we experience throughout our lives. The Klimecki lab studies diseases resulting from human exposure to arsenic, contributing to a better understanding of the inherited genetic differences between people that result in altered chemical processing of arsenic after it enters the body.

Research Interest

Walter T. Klimecki, DVM, PhD, is an Associate Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona. Dr. Klimecki holds joint appointments in the College of Medicine, the College of Public Health, and the Arizona Respiratory Center. He is a Full Member of the Southwest Environmental Health Sciences Center (SWEHSC) where, together with BIO5 director Martinez and BIO5 Statistics Consulting Service director Billheimer, he leads the Integrative Health Sciences (IHS) Center at SWEHSC. The IHS is a translational research support core at SWEHSC, focused on lowering the “activation energy” for translational research.Dr. Klimecki’s research focuses on the toxicology of metals in the environment, an issue particularly relevant in our mining-intensive state. His research work has encompassed a wide range of experimental approaches, from epidemiological studies of arsenic-exposed human populations, to laboratory models including cell culture and rodents. Using cutting edge genetics tools, Dr. Klimecki’s group recently published the first report of an association between human ancestry and response to environmental toxicants. In this provocative work, his group found that individuals whose genomes were comprised of DNA with its origins in the indigenous American populations processed ingested arsenic in a less harmful manner than did individuals whose genomes had their origins in Europe. Using laboratory models his group made ground-breaking discoveries of the impact of arsenic exposure on a process known as autophagy, in which cells digest parts of their own machinery in a sort of “cash for clunkers” arrangement. The ability of arsenic to perturb this process is only now being appreciated by the toxicology community, thanks to the work of the Klimecki Lab. Dr. Klimecki was recently elected as a Vice President-elect to the Metals Specialty Section of the Society of Toxicology, the preeminent scientific toxicology organization in the world. Dr. Klimecki’s research is highly collaborative: his grants and publications have included many BIO5 members, including BIO5 director Fernando Martinez, and BIO5 members Donata Vercelli, Dean Billheimer, and Marilyn Halonen.

Publications

Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., Adhihetty, P. J., Adler, S. G., Agam, G., Agarwal, R., Aghi, M. K., Agnello, M., Agostinis, P., Aguilar, P. V., Aguirre-Ghiso, J., , Airoldi, E. M., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1-222.
BIO5 Collaborators
Yin Chen, Walter Klimecki
Beamer, P. -., Sugeng, A. J., Kelly, M. D., Lothrop, N., Klimecki, W. -., Wilkinson, S. T., & Loh, M. M. (2014). Use of dust fall filters as passive samplers for metal concentrations in air for communities near contaminated mine tailings. Environmental Science Processes and Impacts, 16(6), 1157-1536.
BIO5 Collaborators
Paloma Beamer, Walter Klimecki
Cherrington, N., Canet, M. J., Hardwick, R. N., Lake, A. D., Kopplin, M. J., Scheffer, G. L., Klimecki, W. T., Gandolfi, A. J., & Cherrington, N. J. (2012). Altered arsenic disposition in experimental nonalcoholic fatty liver disease. Drug metabolism and disposition: the biological fate of chemicals, 40(9).
BIO5 Collaborators
Nathan J Cherrington, Walter Klimecki

Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH.

Lothrop, N. Z., Wilkinson, S. T., Verhougstraete, M., Sugeng, A., Loh, M. M., Klimecki, W., & Beamer, P. I. (2015). Home Water Treatment Habits and Effectiveness in a Rural Arizona Community. Water, 7(3), 1217-1231.
BIO5 Collaborators
Paloma Beamer, Walter Klimecki
Cherrington, N., Lake, A. D., Novak, P., Hardwick, R. N., Flores-Keown, B., Zhao, F., Klimecki, W. T., & Cherrington, N. J. (2013). The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease. Toxicological sciences : an official journal of the Society of Toxicology.
BIO5 Collaborators
Nathan J Cherrington, Walter Klimecki

Nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to severe, nonalcoholic steatohepatitis (NASH) in 7-14% of the U.S. population through a 2(nd) 'hit' in the form of increased oxidative stress and inflammation. ER stress signaling and the unfolded protein response (UPR) are triggered when high levels of lipids and misfolded proteins alter ER homeostasis creating a lipotoxic environment within NAFLD livers. The objective of this study was to determine the coordinate regulation of ER stress-associated genes in the progressive stages of human NAFLD. Human liver samples categorized as normal, steatosis, NASH (Fatty) and NASH (Not Fatty) were analyzed by individual Affymetrix GeneChip Human 1.0ST microarrays, immunoblots, and immunohistochemistry. A gene set enrichment analysis was performed on autophagy, apoptosis, lipogenesis and ER stress/UPR gene categories. An enrichment of downregulated genes in the ER stress associated-lipogenesis and ER stress/UPR gene categories was observed in NASH. Conversely, an enrichment of upregulated ER stress-associated genes for autophagy and apoptosis gene categories was observed in NASH. Protein expression of the adaptive liver response protein STC2 and the transcription factor XBP-1s were significantly elevated among NASH samples while other downstream ER stress proteins including CHOP, ATF4 and phosphorylated JNK and eIF2α were not significantly changed in disease progression. Increased nuclear accumulation of total XBP-1 protein was observed in steatosis and NASH livers. The findings reveal the presence of a coordinated, adaptive transcriptional response to hepatic ER stress in human NAFLD.