Laura Hope Neuschwander Tetri

All Publications

• Short-Term Fasting Alters Mitochondrial Dynamics and Increases Mitochondrial Release From Cardiomyoblasts Tetri, L., Lopez, I., Dey, S., Vijayan, V., Haileselassie, B. LIPPINCOTT WILLIAMS & WILKINS. 2025: 1074

  View details for Web of Science ID 001551889100412

• Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy. Life sciences Li, S. J., Tetri, L. H., Vijayan, V., Elezaby, A., Chiang, C. H., Lopez, I., Ostberg, N. P., Cornell, T. T., Chen, C. Y., Haileselassie, B. 2025: 123658

  Abstract

  Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release in vitro. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. In vivo, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both in vitro and in vivo.P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.

  View details for DOI 10.1016/j.lfs.2025.123658

  View details for PubMedID 40287058

• Altered profiles of extracellular mitochondrial DNA in immunoparalyzed pediatric patients after thermal injury. Shock (Augusta, Ga.) Tetri, L. H., Penatzer, J. A., Tsegay, K. B., Tawfik, D. S., Burk, S., Lopez, I., Thakkar, R. K., Haileselassie, B. 2023

  Abstract

  Thermal injury is a major cause of morbidity and mortality in the pediatric population world-wide with secondary infection being the most common acute complication. Suppression of innate and adaptive immune function is predictive of infection in pediatric burn patients, but little is known about the mechanisms causing these effects. Circulating mtDNA which induces a proinflammatory signal, has been described in multiple disease states, but has not been studied in pediatric burn injuries. This study examined the quantity of circulating mtDNA and mtDNA mutations in immunocompetent (IC) and immunoparalyzed (IP) pediatric burn patients.Circulating DNA was isolated from plasma of pediatric burn patients treated at Nationwide Children's Hospital Burn Center at early (1-3 days) and late (4-7 days) time points post-injury. These patients were categorized as IP or IC based on previously established immune function testing and secondary infection. Three mitochondrial genes, D loop, ND1, and ND4, were quantified by multiplexed qPCR to assess both mtDNA quantity and mutation load.At the early timepoint, there were no differences in plasma mtDNA quantity, however IC patients had a progressive increase in mtDNA over time when compared to IP patients (change in ND1 copy number over time 3880 vs 87 copies/day, p = 0.0004). Conversely, the IP group had an increase in mtDNA mutation burden over time.IC patients experienced a significant increase in circulating mtDNA quantity over time, demonstrating an association between increased mtDNA release, and proinflammatory phenotype in the burn patients. IP patients had significant increases in mtDNA mutation load likely representative of degree of oxidative damage. Together, these data provide further insight into the inflammatory and immunological mechanisms following pediatric thermal injury.

  View details for DOI 10.1097/SHK.0000000000002253

  View details for PubMedID 38010095

• Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy. Journal of molecular and cellular cardiology Mukherjee, R., Tetri, L. H., Li, S. J., Fajardo, G., Ostberg, N. P., Tsegay, K. B., Gera, K., Cornell, T. T., Bernstein, D., Mochly-Rosen, D., Haileselassie, B. 2023; 177: 28-37

  Abstract

  Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis.H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin μ, PFTμ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype.Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTμ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTμ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival.Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.

  View details for DOI 10.1016/j.yjmcc.2023.01.008

  View details for PubMedID 36841153

• DRP1/P53 INTERACTION PLAYS A KEY ROLE IN MITOCHONDRIAL DYSFUNCTION OF SEPTIC CARDIOMYOPATHY Tetri, L., Mukherjee, R., Li, S., Fajardo, G., Ostberg, N., Tsegay, K., Gera, K., Cornell, T., Bernstein, D., Mochly-Rosen, D., Haileselassie, B. LIPPINCOTT WILLIAMS & WILKINS. 2023: 617

  View details for Web of Science ID 000921450901535

• MITOCHONDRIAL FISSION & CELL-FREE MITOCHONDRIA MEDIATE CARDIAC DYSFUNCTION IN OBESITY CARDIOMYOPATHY Li, S., Chen, C., Ostberg, N., Tetri, L., Cornell, T., Mochly-Rosen, D., Haileselassie, B. LIPPINCOTT WILLIAMS & WILKINS. 2023: 50

  View details for Web of Science ID 000921450900100

• Blunted cardiac output response to exercise in adolescents born preterm. European journal of applied physiology Haraldsdottir, K., Watson, A. M., Pegelow, D. F., Palta, M., Tetri, L. H., Levin, T., Brix, M. D., Centanni, R. M., Goss, K. N., Eldridge, M. M. 2020; 120 (11): 2547-2554

  Abstract

  Premature birth is associated with lasting effects, including lower exercise capacity and pulmonary function, and is acknowledged as a risk factor for cardiovascular disease. The aim was to evaluate factors affecting exercise capacity in adolescents born preterm, including the cardiovascular and pulmonary responses to exercise, activity level and strength.21 preterm-born and 20 term-born adolescents (age 12-14 years) underwent strength and maximal exercise testing with thoracic bioimpedance monitoring. Baseline variables were compared between groups and ANCOVA was used to compare heart rate, cardiac output (Q) and stroke volume (SV) during exercise between groups while adjusting for body surface area.Preterm-borns had lower maximal aerobic capacity than term-borns (2.0 ± 0.5 vs. 2.5 ± 0.5 L/min, p = 0.01) and lower maximal power (124 ± 26 vs. 153 ± 33 watts, p < 0.01), despite similar physical activity scores. Pulmonary function and muscular strength did not differ significantly. Although baseline Q and SV did not differ between groups, preterm adolescents had significantly lower cardiac index (Qi) at 50, 75 and 100% of maximal time to exhaustion, driven by SV volume index (SVi, 50% max time: 53.0 ± 9.0 vs. 61.6 ± 11.4; 75%: 51.7 ± 8.4 vs. 64.3 ± 11.1; 100%: 51.2 ± 9.3 vs. 64.3 ± 11.5 ml/m2, all p < 0.01), with similar heart rates.Otherwise healthy and physically active adolescents born very preterm exhibit lower exercise capacity than term-born adolescents. Despite similar baseline cardiovascular values, preterm-born adolescents demonstrate significantly reduced Qi and SVi during incremental and maximal exercise.

  View details for DOI 10.1007/s00421-020-04480-9

  View details for PubMedID 32862247

• RET receptor expression and interaction with TRK receptors in neuroblastomas. Oncology reports Tetri, L. H., Kolla, V., Golden, R. L., Iyer, R., Croucher, J. L., Choi, J. H., Macfarland, S. P., Naraparaju, K., Guan, P., Nguyen, F., Gaonkar, K. S., Raman, P., Brodeur, G. M. 2020; 44 (1): 263-272

  Abstract

  Neuroblastomas (NBs) have heterogeneous clinical behavior, from spontaneous regression or differentiation to relentless progression. Evidence from our laboratory and others suggests that neurotrophin receptors contribute to these disparate behaviors. Previously, the role of TRK receptors in NB pathogenesis was investigated. In the present study, the expression of RET and its co‑receptors in a panel of NB cell lines was investigated and responses to cognate ligands GDNF, NRTN, and ARTN with GFRα1‑3 co‑receptor expression, respectively were found to be correlated. RET expression was high in NBLS, moderate in SY5Y, low/absent in NBEBc1 and NLF cells. All cell lines expressed at least one of GFRα co‑receptors. In addition, NBLS, SY5Y, NBEBc1 and NLF cells showed different morphological changes in response to ligands. As expected, activation of RET/GFRα3 by ARTN resulted in RET phosphorylation. Interestingly, activation of TrkA by its cognate ligand NGF resulted in RET phosphorylation at Y905, Y1015, and Y1062, and this was inhibited in a dose‑dependent manner by the TRK inhibitor (CEP‑701). Conversely, RET activation by ARTN in NBLS cells led to phosphorylation of TrkA. This suggests a physical association between RET and TRK proteins, and cross‑talk between these two receptor pathways. Finally, RET, GFR and TRK expression in primary tumors was investigated and a significant association between RET, its co‑receptors and TRK expression was demonstrated. Thus, the present data support a complex model of interacting neurotrophin receptor pathways in the regulation of cell growth and differentiation in NBs.

  View details for DOI 10.3892/or.2020.7583

  View details for PubMedID 32319659

• Bimodal right ventricular dysfunction after postnatal hyperoxia exposure: implications for the preterm heart. American journal of physiology. Heart and circulatory physiology Kumari, S., Braun, R. K., Tetri, L. H., Barton, G. P., Hacker, T. A., Goss, K. N. 2019; 317 (6): H1272-H1281

  Abstract

  Rats exposed to postnatal hyperoxia develop right ventricular (RV) dysfunction, mild pulmonary hypertension, and dysregulated cardiac mitochondrial biogenesis when aged to one year, with the degree of cardiac dysfunction and pulmonary hypertension similar to that previously described in young adults born preterm. Here, we sought to understand the impact of postnatal hyperoxia exposure on RV hemodynamic and mitochondrial function across the life span. In Methods, pups from timed-pregnant Sprague-Dawley rats were randomized to normoxia or hyperoxia [fraction of inspired oxygen (FIO2), 0.85] exposure for the first 14 days of life, a commonly used model of chronic lung disease of prematurity. RV hemodynamic and mitochondrial function were assessed by invasive measurement of RV pressure-volume loops and by high-resolution respirometry at postnatal day 21 (P21), P90, and P365. In Results, at P21, hyperoxia-exposed rats demonstrated severe pulmonary hypertension and RV dysfunction, accompanied by depressed mitochondrial oxidative capacity. However, significant upregulation of mitochondrial biogenesis at P21 as well as improved afterload led to complete RV hemodynamic and mitochondrial recovery at P90. Mitochondrial DNA mutations were significantly higher by P90 and associated with significant late RV mitochondrial and hemodynamic dysfunction at P365. In conclusion, there appears to be a "honeymoon period" where cardiac hemodynamic and mitochondrial function normalizes following postnatal hyperoxia exposure, only to decline again with ongoing aging. This finding may have significant implications if a long-term pulmonary vascular screening program were to be developed for children or adults with a history of severe prematurity. Further investigation into the mechanisms of recovery are warranted.NEW & NOTEWORTHY Premature birth is associated with increased risk for cardiac dysfunction and failure throughout life. Here, we identify bimodal right ventricular dysfunction after postnatal hyperoxia exposure. Mitochondrial biogenesis serves as an early adaptive feature promoting recovery of cardiac hemodynamic and mitochondrial function. However, the accumulation of mitochondrial DNA mutations results in late mitochondrial and right ventricular dysfunction. This bimodal right ventricular dysfunction may have important implications for the development of screening programs in the preterm population.

  View details for DOI 10.1152/ajpheart.00383.2019

  View details for PubMedID 31702968

  View details for PubMedCentralID PMC6962619

• Heart rate recovery after maximal exercise is impaired in healthy young adults born preterm. European journal of applied physiology Haraldsdottir, K., Watson, A. M., Beshish, A. G., Pegelow, D. F., Palta, M., Tetri, L. H., Brix, M. D., Centanni, R. M., Goss, K. N., Eldridge, M. W. 2019; 119 (4): 857-866

  Abstract

  The long-term implications of premature birth on autonomic nervous system (ANS) function are unclear. Heart rate recovery (HRR) following maximal exercise is a simple tool to evaluate ANS function and is a strong predictor of cardiovascular disease. Our objective was to determine whether HRR is impaired in young adults born preterm (PYA).Individuals born between 1989 and 1991 were recruited from the Newborn Lung Project, a prospectively followed cohort of subjects born preterm weighing < 1500 g with an average gestational age of 28 weeks. Age-matched term-born controls were recruited from the local population. HRR was measured for 2 min following maximal exercise testing on an upright cycle ergometer in normoxia and hypoxia, and maximal aerobic capacity (VO2max) was measured.Preterms had lower VO2max than controls (34.88 ± 5.24 v 46.15 ± 10.21 ml/kg/min, respectively, p < 0.05), and exhibited slower HRR compared to controls after 1 and 2 min of recovery in normoxia (absolute drop of 20 ± 4 v 31 ± 10 and 41 ± 7 v 54 ± 11 beats per minute (bpm), respectively, p < 0.01) and hypoxia (19 ± 5 v 26 ± 8 and 39 ± 7 v 49 ± 13 bpm, respectively, p < 0.05). After adjusting for VO2max, HRR remained slower in preterms at 1 and 2 min of recovery in normoxia (21 ± 2 v 30 ± 2 and 42 ± 3 v 52 ± 3 bpm, respectively, p < 0.05), but not hypoxia (19 ± 3 v 25 ± 2 and 40 ± 4 v 47 ± 3 bpm, respectively, p > 0.05).Autonomic dysfunction as seen in this study has been associated with increased rates of cardiovascular disease in non-preterm populations, suggesting further study of the mechanisms of autonomic dysfunction after preterm birth.

  View details for DOI 10.1007/s00421-019-04075-z

  View details for PubMedID 30635708

  View details for PubMedCentralID PMC7100254

• Early Pulmonary Vascular Disease in Young Adults Born Preterm. American journal of respiratory and critical care medicine Goss, K. N., Beshish, A. G., Barton, G. P., Haraldsdottir, K., Levin, T. S., Tetri, L. H., Battiola, T. J., Mulchrone, A. M., Pegelow, D. F., Palta, M., Lamers, L. J., Watson, A. M., Chesler, N. C., Eldridge, M. W. 2018; 198 (12): 1549-1558

  Abstract

  Rationale: Premature birth affects 10% of live births in the United States and is associated with alveolar simplification and altered pulmonary microvascular development. However, little is known about the long-term impact prematurity has on the pulmonary vasculature.Objectives: Determine the long-term effects of prematurity on right ventricular and pulmonary vascular hemodynamics.Methods: Preterm subjects (n = 11) were recruited from the Newborn Lung Project, a prospectively followed cohort at the University of Wisconsin-Madison, born preterm with very low birth weight (≤1,500 g; average gestational age, 28 wk) between 1988 and 1991. Control subjects (n = 10) from the same birth years were recruited from the general population. All subjects had no known adult cardiopulmonary disease. Right heart catheterization was performed to assess right ventricular and pulmonary vascular hemodynamics at rest and during hypoxic and exercise stress.Measurements and Main Results: Preterm subjects had higher mean pulmonary arterial pressures (mPAPs), with 27% (3 of 11) meeting criteria for borderline pulmonary hypertension (mPAP, 19-24 mm Hg) and 18% (2 of 11) meeting criteria for overt pulmonary hypertension (mPAP ≥ 25 mm Hg). Pulmonary vascular resistance and elastance were higher at rest and during exercise, suggesting a stiffer vascular bed. Preterm subjects were significantly less able to augment cardiac index or right ventricular stroke work during exercise. Among neonatal characteristics, total ventilatory support days was the strongest predictor of adult pulmonary pressure.Conclusions: Young adults born preterm demonstrate early pulmonary vascular disease, characterized by elevated pulmonary pressures, a stiffer pulmonary vascular bed, and right ventricular dysfunction, consistent with an increased risk of developing pulmonary hypertension.

  View details for DOI 10.1164/rccm.201710-2016OC

  View details for PubMedID 29944842

  View details for PubMedCentralID PMC6298636

• Sex-Specific Skeletal Muscle Fatigability and Decreased Mitochondrial Oxidative Capacity in Adult Rats Exposed to Postnatal Hyperoxia. Frontiers in physiology Tetri, L. H., Diffee, G. M., Barton, G. P., Braun, R. K., Yoder, H. E., Haraldsdottir, K., Eldridge, M. W., Goss, K. N. 2018; 9: 326

  Abstract

  Premature birth affects more than 10% of live births, and is characterized by relative hyperoxia exposure in an immature host. Long-term consequences of preterm birth include decreased aerobic capacity, decreased muscular strength and endurance, and increased prevalence of metabolic diseases such as type 2 diabetes mellitus. Postnatal hyperoxia exposure in rodents is a well-established model of chronic lung disease of prematurity, and also recapitulates the pulmonary vascular, cardiovascular, and renal phenotype of premature birth. The objective of this study was to evaluate whether postnatal hyperoxia exposure in rats could recapitulate the skeletal and metabolic phenotype of premature birth, and to characterize the subcellular metabolic changes associated with postnatal hyperoxia exposure, with a secondary aim to evaluate sex differences in this model. Compared to control rats, male rats exposed to 14 days of postnatal hyperoxia then aged to 1 year demonstrated higher skeletal muscle fatigability, lower muscle mitochondrial oxidative capacity, more mitochondrial damage, and higher glycolytic enzyme expression. These differences were not present in female rats with the same postnatal hyperoxia exposure. This study demonstrates detrimental mitochondrial and muscular outcomes in the adult male rat exposed to postnatal hyperoxia. Given that young adults born premature also demonstrate skeletal muscle dysfunction, future studies are merited to determine whether this dysfunction as well as reduced aerobic capacity is due to reduced mitochondrial oxidative capacity and metabolic dysfunction.

  View details for DOI 10.3389/fphys.2018.00326

  View details for PubMedID 29651255

  View details for PubMedCentralID PMC5884929

• Impaired autonomic function in adolescents born preterm. Physiological reports Haraldsdottir, K., Watson, A. M., Goss, K. N., Beshish, A. G., Pegelow, D. F., Palta, M., Tetri, L. H., Barton, G. P., Brix, M. D., Centanni, R. M., Eldridge, M. W. 2018; 6 (6): e13620

  Abstract

  Preterm birth temporarily disrupts autonomic nervous system (ANS) development, and the long-term impacts of disrupted fetal development are unclear in children. Abnormal cardiac ANS function is associated with worse health outcomes, and has been identified as a risk factor for cardiovascular disease. We used heart rate variability (HRV) in the time domain (standard deviation of RR intervals, SDRR; and root means squared of successive differences, RMSSD) and frequency domain (high frequency, HF; and low frequency, LF) at rest, as well as heart rate recovery (HRR) following maximal exercise, to assess autonomic function in adolescent children born preterm. Adolescents born preterm (less than 36 weeks gestation at birth) in 2003 and 2004 and healthy age-matched full-term controls participated. Wilcoxon Rank Sum tests were used to compare variables between control and preterm groups. Twenty-one adolescents born preterm and 20 term-born controls enrolled in the study. Preterm-born subjects had lower time-domain HRV, including SDRR (69.1 ± 33.8 vs. 110.1 ± 33.0 msec, respectively, P = 0.008) and RMSSD (58.8 ± 38.2 vs. 101.5 ± 36.2 msec, respectively, P = 0.012), with higher LF variability in preterm subjects. HRR after maximal exercise was slower in preterm-born subjects at 1 min (30 ± 12 vs. 39 ± 9 bpm, respectively, P = 0.013) and 2 min (52 ± 10 vs. 60 ± 10 bpm, respectively, P = 0.016). This study is the first report of autonomic dysfunction in adolescents born premature. Given prior association of impaired HRV with adult cardiovascular disease, additional investigations into the mechanisms of autonomic dysfunction in this population are warranted.

  View details for DOI 10.14814/phy2.13620

  View details for PubMedID 29595875

  View details for PubMedCentralID PMC5875539

• Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis. American journal of respiratory cell and molecular biology Goss, K. N., Kumari, S., Tetri, L. H., Barton, G., Braun, R. K., Hacker, T. A., Eldridge, M. W. 2017; 56 (5): 609-619

  Abstract

  Prematurity complicates 12% of births, and young adults with a history of prematurity are at risk to develop right ventricular (RV) hypertrophy and impairment. The long-term risk for pulmonary vascular disease, as well as mechanisms of RV dysfunction and ventricular-vascular uncoupling after prematurity, remain poorly defined. Using an established model of prematurity-related lung disease, pups from timed-pregnant Sprague Dawley rats were randomized to normoxia or hyperoxia (fraction of inspired oxygen, 0.85) exposure for the first 14 days of life. After aging to 1 year in standard conditions, rats underwent hemodynamic assessment followed by tissue harvest for biochemical and histological evaluation. Aged hyperoxia-exposed rats developed significantly greater RV hypertrophy, associated with a 40% increase in RV systolic pressures. Although cardiac index was similar, hyperoxia-exposed rats demonstrated a reduced RV ejection fraction and significant RV-pulmonary vascular uncoupling. Hyperoxia-exposed RV cardiomyocytes demonstrated evidence of mitochondrial dysregulation and mitochondrial DNA damage, suggesting potential mitochondrial dysfunction as a cause of RV dysfunction. Aged rats exposed to postnatal hyperoxia recapitulate many features of young adults born prematurely, including increased RV hypertrophy and decreased RV ejection fraction. Our data suggest that postnatal hyperoxia exposure results in mitochondrial dysregulation that persists into adulthood with eventual RV dysfunction. Further evaluation of long-term mitochondrial function is warranted in both animal models of premature lung disease and in human adults who were born preterm.

  View details for DOI 10.1165/rcmb.2016-0256OC

  View details for PubMedID 28129517

  View details for PubMedCentralID PMC5449491

• Dietary trans-fatty acid induced NASH is normalized following loss of trans-fatty acids from hepatic lipid pools. Lipids Neuschwander-Tetri, B. A., Ford, D. A., Acharya, S., Gilkey, G., Basaranoglu, M., Tetri, L. H., Brunt, E. M. 2012; 47 (10): 941-50

  Abstract

  Previous experiments in mice showed that dietary trans-fats could play a role in non-alcoholic steatohepatitis (NASH) yet little is known about the accumulation trans-fats in hepatic lipid pools in relationship to liver injury. NASH is also associated with obesity yet improves with only modest weight loss. To distinguish the role of obesity versus sustained consumption of a trans-fat containing diet in causing NASH, mice with obesity and NASH induced by consuming a high trans-fat diet for 16 weeks were subsequently fed standard chow or maintained on trans-fat chow for another 8 weeks. The accumulation, partitioning and loss of trans-fats in the major hepatic lipid pools during and after trans-fat consumption were determined. Obese mice switched to standard chow remained obese but steatohepatitis improved. trans-fats were differentially incorporated into the major hepatic lipid pools and the loss of trans-fats after crossover to control chow was greatest in the cholesteryl ester pool. In summary, dietary changes can improve the biochemical and histopathological changes of NASH despite persistent obesity in mice. Analysis of hepatic lipids confirmed that dietary trans-fats accumulate in the major lipid pools and are released differentially with diet normalization. The substantial loss of trans-fats from the cholesteryl ester pool in parallel with improvement in NASH suggests that this pool of trans-fats could play a role in the pathogenesis of NASH.

  View details for DOI 10.1007/s11745-012-3709-7

  View details for PubMedID 22923371

  View details for PubMedCentralID PMC3473077

• A mechanism by which dietary trans fats cause atherosclerosis. The Journal of nutritional biochemistry Chen, C. L., Tetri, L. H., Neuschwander-Tetri, B. A., Huang, S. S., Huang, J. S. 2011; 22 (7): 649-55

  Abstract

  Dietary trans fats (TFs) have been causally linked to atherosclerosis, but the mechanism by which they cause the disease remains elusive. Suppressed transforming growth factor (TGF)-β responsiveness in aortic endothelium has been shown to play an important role in the pathogenesis of atherosclerosis in animals with hypercholesterolemia. We investigated the effects of a high TF diet on TGF-β responsiveness in aortic endothelium and integration of cholesterol in tissues. Here, we show that normal mice fed a high TF diet for 24 weeks exhibit atherosclerotic lesions and suppressed TGF-β responsiveness in aortic endothelium. The suppressed TGF-β responsiveness is evidenced by markedly reduced expression of TGF-β type I and II receptors and profoundly decreased levels of phosphorylated Smad2, an important TGF-β response indicator, in aortic endothelium. These mice exhibit greatly increased integration of cholesterol into tissue plasma membranes. These results suggest that dietary TFs cause atherosclerosis, at least in part, by suppressing TGF-β responsiveness. This effect is presumably mediated by the increased deposition of cholesterol into cellular plasma membranes in vascular tissue, as in hypercholesterolemia.

  View details for DOI 10.1016/j.jnutbio.2010.05.004

  View details for PubMedID 21036587

  View details for PubMedCentralID PMC3125015

• Protective role of angiotensin II type 2 receptor signaling in a mouse model of pancreatic fibrosis. American journal of physiology. Gastrointestinal and liver physiology Ulmasov, B., Xu, Z., Tetri, L. H., Inagami, T., Neuschwander-Tetri, B. A. 2009; 296 (2): G284-94

  Abstract

  The renin-angiotensin system contributes to pathological processes in a variety of organs. In the pancreas, blocking the angiotensin II (AII) type 1 receptor (AT1) attenuates pancreatic fibrogenesis in animal models of pancreatitis. Because the role of the AII type 2 receptor (AT2) in modulating pancreatic injury is unknown we investigated the role of AT2 in pancreatic injury and fibrosis. Pancreatic fibrosis was induced by repetitive cerulein administration in C57BL/6 wild-type (WT) or AT2-deficient (AT2-/-) mice and assessed by morphology and gene expression at 10 days. There was no difference between WT and AT2-/- mice in the degree of acute pancreatic injury as assessed by amylase release at 9 and 12 h and by histological examination of the pancreas at 12 h. In contrast, parenchymal atrophy and fibrosis were more pronounced in AT2-/- mice compared with WT mice at 10 days. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for alpha-smooth muscle actin and by immunocytochemistry; PSC activation was further increased in AT2-/- mice compared with WT mice. The level of pancreatic transforming growth factor-beta1 mRNA and protein after repetitive cerulein treatment was higher in AT2-/- mice than in WT mice. Our results demonstrate that, in contrast to AT1 receptor signaling, AT2 receptor signaling modulates protective antifibrogenic effects in a mouse model of cerulein-induced pancreatic fibrogenesis. We propose that the effects of AII on injury-induced pancreatic fibrosis may be determined by the balance between AT1 and AT2 receptor signaling.

  View details for DOI 10.1152/ajpgi.90409.2008

  View details for PubMedID 19033539

  View details for PubMedCentralID PMC2643909

• Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. American journal of physiology. Gastrointestinal and liver physiology Tetri, L. H., Basaranoglu, M., Brunt, E. M., Yerian, L. M., Neuschwander-Tetri, B. A. 2008; 295 (5): G987-95

  Abstract

  The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

  View details for DOI 10.1152/ajpgi.90272.2008

  View details for PubMedID 18772365

  View details for PubMedCentralID PMC4059366