Associate Professor, Anesthesiology
- BS in Engineering Physics, University of Colorado, Boulder, CO
- MS, PhD California Institute of Technology, Pasadena, CA
- Postdoctoral Fellowship, National Jewish Health, Denver, CO
- Postdoctoral Fellowship, University of Colorado, Boulder, CO
Mail Stop 8130
Research Complex 1 South
12801 E. 17th Avenue, Rm L18-7403G
Aurora, CO 80045
Telephone: (303) 724-3979
- Role of the macrophage in developmental programming of nonalcoholic fatty liver disease and mechanisms by which the dietary antioxidant, pyrroloquinoline quinone (PQQ), prevents liver injury
- Effect of microgravity on liver lipid metabolism
- Maternal obesity and consumption of a Western-style diet (WSD) increases risk for offspring obesity and severe liver disease. Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide,
affecting over 30% of obese children, 80% of obese adults and 40% of all adults in the US. The pathophysiology of NAFLD has not been resolved, but compelling data in animals and humans show consistent links between
exposure to maternal obesity/WSD and childhood NAFLD, resulting in rapid progression to nonalcoholic steatohepatitis (NASH) and fibrosis in offspring. While these studies demonstrate that risk factors for human pediatric
obesity/NAFLD begin in utero, little is known about gestational factors responsible for driving this phenotype, importance of timing of the exposure, and the relative permanence or plasticity of the response. Using
16S sequencing of the microbiota, we observed that offspring from WSD-exposed dams develop early gut dysbiosis that persists into adulthood. This effect is associated with skewing of bone marrow-derived macrophages
(BMDM) and liver macrophages towards a pro-inflammatory phenotype and increased susceptibility to NASH, even after diet withdrawal at weaning, assessed by flow cytometry, metabolomics, and qPCR for inflammatory
gene expression. Hepatic macrophages from offspring of WSD-fed dams are metabolically reprogrammed toward a pro-inflammatory phenotype (elevated IL-1β) and in the absence of hypoxia-inducible factor (HIF)-1α, we
found that macrophages from WSD-fed mice adopt a resolving phenotype (elevated IL-10). Further, we recently demonstrated that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant found in high concentration
in human breast milk, when administered to WSD-fed dams only during gestation and lactation, prevented early microbial dysbiosis, hepatic macrophage accumulation, and NAFLD/fibrosis in adult offspring. In vitro,
PQQ restored macrophage metabolism and decreased glycolysis, consistent with a reparative macrophage phenotype. Our hypothesis is that maternal transmission of dysbiotic microbes are causal for HIF-1α-mediated
macrophage remodeling to a pro-inflammatory phenotype, leading to development of NASH in the offspring. Furthermore, we hypothesize that PQQ, by restoring macrophage metabolism and promoting a healthier microbiome
during critical developmental windows, prevents development of NASH. Our ongoing studies are aimed at testing causality between maternal WSD, offspring dysbiosis and development of disordered macrophage metabolism,
leading to NASH, and testing a safe nutritional countermeasure aimed at halting developmental programming of NAFLD in the pediatric population.
- Astronauts embarking on long duration spaceflight missions will be exposed to multiple and potentially synergistic risks, two of which are exposure to altered inertial forces (gravity) and long-term exposure
to low-dose/low-dose-rate radiation. In previous studies using spaceflight and simulated spaceflight (hindlimb unloading and/or space-like radiation), increased oxidative stress and activation of the inflammatory
response were identified as major contributors to physiological changes associated with spaceflight, including alterations to the cardiovascular system, the musculoskeletal system, metabolism and the liver. In
previous studies, we have found that spaceflight results in significant alterations to bone marrow stem cell populations, including down-regulation of the hematological system and cellular development. We have
also observed significant alterations to liver lipid metabolism, including increased accumulation of triglycerides and decreased retinoids, with up regulation of pro-fibrotic programs suggesting early liver
injury in mice results from only two weeks of exposure to the space environment. An increase in populations of pro-inflammatory macrophages has been observed in multiple spaceflight experiments; we postulate
this results from activation of inflammatory pathways in bone marrow populations during spaceflight exposure, leading to phenotypic shifts in hematopoietic stem cells and monocyte activation. Our studies
using models of simulated spaceflight (hindlimb unloading and low dose/low dose rate radiation) are aimed at elucidating mechanisms by which the space environment regulates activation of pro-inflammatory
macrophages and promotes liver injury, including steatosis and fibrotic scarring. Furthermore, we aim to assess the effectiveness of a dietary countermeasure available for over-the-counter human use,
coenzyme pyrroloquinoline quinone (PQQ), on mitigating the observed activation of hepatic inflammation and the hypothesized activation of pro-inflammatory macrophages (and resulting liver damage) in
response to simulated spaceflight conditions.
- Friedman, JE, Dobrinskikh, E, Alfonso-Garcia, A, Fast, A, Janssen, RC, Soderborg, TK, Anderson, AL, Reisz, JA, D'Alessandro, A, Frank, DN, Robertson, CE, de la Houssaye, BA, Johnson, LK, Orlicky, DJ, Wang, X X, Levi, M, Potma, EO, El Kasmi, KC, Jonscher, KR, PQQ prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in obese mice. Hepatol Commun. (2018); Jan 22;2(3):313-328. PMID:29507905 PMCID:PMC5831029.
- Blaber EA, Pecaut MJ, Jonscher KR. Spaceflight Activates Autophagy Programs and the Proteasome in Mouse Liver. Int J Mol Sci. 2017 Sep 27;18(10)PubMed PMID: 28953266.
- Jonscher KR, Stewart MS, Alfonso-Garcia A, DeFelice BC, Wang XX, Luo Y, Levi M, Heerwagen MJ, Janssen RC, de la Houssaye BA, Wiitala E, Florey G, Jonscher RL, Potma EO, Fiehn O, Friedman JE. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. FASEB J. 2017 Apr;31(4):1434-1448. PubMed PMID: 28007783; PubMed Central PMCID: PMC5349805.
- Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol. 2017 Feb;14(2):81-96. PubMed PMID: 27780972.
- Pecaut MJ, Mao XW, Bellinger DL, Jonscher KR, Stodieck LS, Ferguson VL, Bateman TA, Mohney RP, Gridley DS. Is spaceflight-induced immune dysfunction linked to systemic changes in metabolism?. PLoS One. 2017;12(5):e0174174. PubMed PMID: 28542224; PubMed Central PMCID: PMC5443495.
- Jonscher KR, Alfonso-Garcia A, Suhalim JL, Orlicky DJ, Potma EO, Ferguson VL, Bouxsein ML, Bateman TA, Stodieck LS, Levi M, Friedman JE, Gridley DS, Pecaut MJ. Spaceflight Activates Lipotoxic Pathways in Mouse Liver. PLoS One. 2016;11(4):e0152877. PubMed PMID: 27097220; PubMed Central PMCID: PMC4838331.
- Choudhury M, Jonscher KR, Friedman JE. Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. Aging (Albany NY). 2011 Feb;3(2):175-8. PubMed PMID: 21386135; PubMed Central PMCID: PMC3082013.
- Kendrick AA, Choudhury M, Rahman SM, McCurdy CE, Friederich M, Van Hove JL, Watson PA, Birdsey N, Bao J, Gius D, Sack MN, Jing E, Kahn CR, Friedman JE, Jonscher KR. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J. 2011 Feb 1;433(3):505-14. PubMed PMID: 21044047; PubMed Central PMCID: PMC3398511.
- Resing KA, Meyer-Arendt K, Mendoza AM, Aveline-Wolf LD, Jonscher KR, Pierce KG, Old WM, Cheung HT, Russell S, Wattawa JL, Goehle GR, Knight RD, Ahn NG. Improving reproducibility and sensitivity in identifying human proteins by shotgun proteomics. Anal Chem. 2004 Jul 1;76(13):3556-68. PubMed PMID: 15228325.
- Jonscher KR and Rucker RB, Pyrroloquinoline Quinone: Its profile and effects on the liver: Implications for health and disease prevention, in Dietary Interventions in Liver Disease, R. Watson, Ed. (2018 in press).
- Bruce K.D. and Jonscher KR, Assessment of Fatty Liver in Models of Disease Programming, Methods Mol Biol. 1735 251-266 (2018) PMID: 29380318.
- Jonscher KR, Jin L., Cambier J.C., Rahman S.M. and Friedman J.E., Targeted proteomics using immunoaffinity purification, Applied Mass Spectroscopy Handbook, M. Lee, Ed. Wiley, NJ pp 3-21 (2011).