Obesity is a complex, multifactorial disease involving an excessive accumulation of body fat that, in time, increases the risk of heart, liver, and kidney diseases, type 2 diabetes, hypertension and certain cancers. Globally around 14%, and in the US 2 in 5 adults, are obese; obesity is the fifth leading risk for global deaths contributing to at least 2.8 million deaths annually.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the hepatic manifestation of obesity and the most common form of liver disease affecting nearly 30% of the US population. The prognosis for simple liver steatosis is relatively benign; however, chronic inflammation and progressive fibrosis may lead to metabolic dysfunction-associated steatohepatitis (MASH) and later to cirrhosis and hepatocellular carcinoma. There is currently only one established treatment to inhibit progression from MASLD to MASH that has been approved by the FDA.
Cardiovascular diseases (CVDs) are the number one cause of death globally. In the United States, about 659,000 people die from CVDs each year, which constitutes one in every four deaths. CVDs costs the United States about $363 billion each year, which includes the cost of health care services, medicines, and lost productivity due to death. Most CVDs are caused by risk factors such as tobacco use, physical inactivity, and obesity.
Despite the increase in the number of cases in the past several decades, the underlying molecular mechanisms of cardiac and hepatic metabolic diseases pathogenesis remain poorly understood, thereby preventing the development of effective diagnostic tools and pharmacotherapies as well as preventive strategies.
RESEARCH
The long-term goal of the Bednarski Lab is to identify metabolic pathways that control the progression of metabolic disorders so that these processes can be targeted in the clinic for disease prevention, diagnosis, or treatment. We use state-of-the-art genomic, transcriptomic, proteomic, metabolomic, and stable isotope tracer methods to establish mechanisms of metabolic disease pathogenesis. In addition to in vitro experiments with primary hepatocytes and cardiomyocyte cell lines, we also use mice with tissue-specific metabolic gene alterations. The in vivo studies involve implementation of the newly developed 13C metabolic flux analysis (MFA) technique, allowing for integrated multi-organ comprehensive quantification of metabolic fluxes.
MFA workflow: a stable isotope or radioactive tracer is introduced into the system being studied. Samples are collected, typically cells and media from an in vitro system or plasma and tissues from an in vivo system. Metabolic enrichment is measured using mass spectrometry. A metabolic network is created based on biochemical equations in a specialized flux software package. Metabolite labeling is simulated for the metabolic network based on the initial guesses, which is then compared to the measured enrichment patterns. Fluxes are readjusted and the process is reiterated until reaching the best fit solution, meaning the simulated labeling matches the measured labeling. The end product of metabolic flux analysis is a network map indicating the fluxes through the system being studied.
Simultaneous in vivo multi-organ fluxomics in obese mice.
OBJECTIVES
Specific objectives of the Bednarski lab are:
Protocol for multi-tissue MFA in conscious, unrestrained mice using a dual catheter system.
Flux map showing cardiac pathways modeled in obese mice. Red arrow indicates increased fluxes relative to normal animals.
- Determine the role of aberrant polyunsaturated fatty acid metabolism in development of lipotoxic cardiomyopathy.
The working hypothesis is that restoration of proper membrane composition will result in the mitigation of cardiometabolic stress and heart dysfunction. - Identify the lipid metabolism pathways associated with diabetic cardiomyopathy pathogenesis.
The working hypothesis is that adjusting fatty acid transport, synthesis, and utilization will alleviate lipotoxic effects and inhibit cardiac steatosis and inflammation. - Ascertain the role of pyruvate metabolism in the progression of steatotic liver disease.
The working hypothesis is that normalization in pyruvate exchange rate between liver and peripheral tissues will contribute to balancing redox state and alleviating oxidative stress leading to improvement of hepatic function. - Characterize the role of acyl-CoA metabolism in steatotic liver disease pathogenesis.
The working hypothesis is that alteration in acyl-CoA synthesis and transport will alleviate metabolic stress and liver disfunction. - Establish if impaired calcium flux and endoplasmic reticulum stress contribute to pancreatic dysfunction and type 2 diabetes advancement.
The working hypothesis is that enhancing the ability of endoplasmic reticulum to sequester calcium will normalize mitochondrial metabolism and reduce pancreatic α- and β-cell lipotoxicity.
Our central hypothesis is that identifying and targeting processes connected with aberrant lipid metabolism will result in the alleviation of lipotoxic effects and the mitigation of metabolic dysfunction. We expect to uncover druggable nodes that can be modulated in vivo with low risk of side effects.
Additionally, we are working on two highly innovative pilot projects:
- Harnessing the potential of epigenetics, we aim to uncover the mechanism behind "healthy obesity" using hibernating 13-lined ground squirrels as a novel model organism.
- Our goal is to assess the impact of Maca (Lepidium meyenii) supplementation on hypothyroidism pathogenesis in vivo.
LAB MEMBERS
My PhD studies at Nencki Institute of Experimental Biology PAS in Warszawa, Poland, focused on the role of long-chain fatty acids metabolism in different models of left ventricular hypertrophy, and have borne fruit in several highly cited publications, a considerable amount of conference proceedings, domestic and EU scientific grants and scholarships, and an international patent. Through my research, I was able to demonstrate for the first time that activation of lipogenesis and fatty acid β-oxidation pathways relate to the development of physiological left ventricular hypertrophy and may be one of the adaptive mechanisms to endurance training. I have also discovered that the excessive accumulation of triglycerides in cardiac muscle, which is associated with pathological left ventricular hypertrophy, is generated by impairment of the lipolytic process. Part of this research was funded by my own pre-doctoral fellowship from the National Science Centre in Poland. Outside of my scientific work, I have devoted myself to science outreach as a re-elected chair of student’s council, organizer of science popularization events and conferences, and a tutor to graduate students.
My commitment to academic and personal excellence led me to postdoctoral training at Vanderbilt University. Throughout my postdoctoral training I have been at the forefront of the field of fluxomics which is emerging as an extremely promising tool in the prevention, diagnosis, and treatment of metabolic diseases. My project focused on the application of in vivo 13C metabolic flux analysis and metabolomics profiling to identify liver phenotypes that accelerate the transition from simple liver steatosis to much more severe steatohepatitis, and to assess in vivo responses to pharmacologic and genetic interventions designed to inhibit this transition. I demonstrated that during chronic, Western diet-induced obesity pharmacological activation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) significantly inhibits NASH progression. I have linked these phenotype improvements to the normalization of pyruvate cycling, alleviation of redox imbalance between liver and peripheral tissues, and increase in hepatic ω-3 polyunsaturated fatty acids content. These findings resulted in several poster and oral presentations at ADA, ASBMB, or FASEB conferences as well as a few publications. For my project assessing liver X receptor (LXR) activation as a strategy to inhibit NASH pathogenesis, I obtained independent financing from the Vanderbilt Diabetes Research and Training Center. I also collaborated with my peers to develop a method allowing for simultaneous in vivo multi-organ metabolic flux analysis. This newly developed, powerful tool allows for whole-body assessment of impaired metabolic fluxes leading to a better understanding of metabolic disorders.
Finally, I am actively participating in the review process of articles for journals specializing in diabetes, hepatology, and lipid metabolism as well as grants for UNL’s Research Council. In addition to my research and service, I am contributing to enhancing the success of students through teaching and mentoring.
During my PhD studies at Nencki Institute of Experimental Biology PAS in Warszawa, Poland, I was focused on molecular and epigenetic mechanism involved in thyroid hormone (TH) action in the heart, especially the role of stearoyl CoA desaturase 1 (SCD1) in those processes. I was investigating molecular and epigenetic mechanisms that affect heart function, structure, and metabolism, particularly lipid metabolism and TH signaling. I showed that TH is an important part of the mechanism of SCD1 in cardiac lipid utilization and may be involved in the upregulation of energetic metabolism that is associated with SCD1 deficiency. Moreover, thanks to my own pre-doctoral financing from National Science Centre in Poland, I was able to demonstrate that SCD1 is involved in the control of epigenetic mechanisms in the heart and may affect gene expression of hormone sensitive lipase (Lipe), enzyme involved in lipolysis pathway, through changes in methylation in its promoter region. During my PhD I was able to attend several workshops in Europe, presented my research at more than 20 conferences around the world and I obtained few awards e.g., FEBS Youth Travel Found Grant.
My further scientific development was continued at Medical University of Bialystok, Poland. In Clinical Research Centre (CRC) I was involved in several scientific projects like PolReD (Stop diabetes! Polish Diabetes Register), GAROS (Genetics of the Acute Response to Oral Semaglutide) and BBSS (Bialystok Bariatric Surgery Study). In CRC I was able to work with medical professionals, develop mitochondria-related analysis techniques, and take part in large-scale human studies and trials.
I graduated from Grinnell College in 2024 with a BA in Biology and concentrations in Statistics and Neuroscience.
As a neuroinformatics intern at the Michigan Neuroscience Institute, University of Michigan, I completed an independent project conducting a meta-analysis looking at changes in gene expression within the anterior cingulate in rats and mice that underwent chronic pain treatment. I presented the results to faculty and fellow lab members at the University of Michigan and at a Grinnell College Biology department seminar.
As a research assistant at Grinnell College within the statistics department, I developed R tutorials for introductory statistics students, beta tested statistics learning material, and coded in R for data visualization. As an undergrad at Grinnell College, some of my research projects included exploring the effects of overexpressing an acid-resistance associated gene in Bacillus subtilis, and observing the localization and dynamics of a protein involved in the anaphase promoting complex in Xenopus embryos using confocal microscopy and Fluorescence Recovery After Photobleaching (FRAP).
FORMER LAB MEMBERS
Yousuf Al-Farqani
2024 Graduate of the University of Nebraska-Lincoln; PhD in Nutrition and Health Sciences with specialization in Biochemical and Molecular Nutrition.
Yousuf's work with the Bednarski Lab included cardiomyocyte phospholipid remodeling in obesity and type 2 diabetes.
PUBLICATIONS, PATENTS, AND GRANTS
Selected Publications
2024
Pharmacological SERCA activation limits diet-induced steatohepatitis and restores liver metabolic function in mice. Bednarski TK, Rahim M, Hasenour CM, Banerjee DR, Trenary IA, Wasserman DH, Young JD; Journal of Lipid Research, 2024; 65 (6): 100558. DOI: 10.1016/j.jlr.2024.100558.
2022
Alterations of lipid metabolism in the heart in spontaneously hypertensive rats precedes left ventricular hypertrophy and cardiac dysfunction. TK Bednarski, MK Duda, P Dobrzyn; Cells 11(19), 3032 1 2022; DOI: 10.3390/cells11193032
2021
Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C–knockout mice. Rahim M, Hasenour CM, Bednarski TK, Hughey CC, Wasserman DH, Young JD; JCI Insight, 2021, 6 (12), e149278; DOI: 10.1172/jcl.insight.149278
In vivo 2H/13C flux analysis in metabolism research. Bednarski TK, Rahim M, Young JD; Current Opinion in Biotechnology 71, 1-8 8; DOI: 10.1013/j.copbio.2021.04.005
2020
Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice. Hasenour CM, Kennedy AJ, Bednarski T, Trenary IA, Eudy BJ, da Silva RP, Boyd KL, Young JD; Journal of Lipid Research, 2020, 61 (5), pp. 707–721; DOI: 10.1194/jlr.RA119000183
2016
Stearoyl-CoA desaturase 1 deficiency reduces lipid accumulation in the heart by activating lipolysis independently of peroxisome proliferator-activated receptor α. Bednarski T, Olichwier A, Opasinska A, Pyrkowska A, Gan AM, Ntambi JM, Dobrzyn P; Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 2016, 1861 (12), pp. 2029–2037; DOI: 10.1016/j.bbalip.2016.10.005
Regulation of cardiac metabolism and function by lipogenic factors [Białkowe czynniki lipogenne - Rola w regulacji metabolizmu i funkcji miȩśnia sercowego]. Bednarski T, Pyrkowska A, Opasinska A, Dobrzyn P; Postepy Higieny i Medycyny Doswiadczalnej, 2016, 70, pp. 644–653; DOI: 10.5604/17322693.1206541
2015
Metabolic reprogramming of the heart through stearoyl-CoA desaturase. Dobrzyn P, Bednarski T, Dobrzyn A; Progress in Lipid Research, 2015, 57, pp. 1–12; DOI: 10.1016/j.plipres.2014.11.003
2013
Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy. Dobrzyn P, Pyrkowska A, Duda MK, Bednarski T, Maczewski M, Langfort J, Dobrzyn A; American journal of physiology. Endocrinology and metabolism, 2013, 304 (12), E1348–1358; DOI: 10.1152/ajpendo.00603.2012
Patents
Method for the early diagnosis of a pre-diabetic state and type 2 diabetes. Dobrzyn P, Dobrzyn A, Kozinski K, Bednarski T; US-10222384-B2
Grants
2024
- ARD Strategic Funding "The impact of Maca (Lepidium meyenii) supplementation on hypothyroidism pathogenesis in vivo."
- CEHS Grand Visions Faculty Seed Grant “Analyzing the impact of steatosis and aberrant lipolysis on epigenetic modifications in cardiomyocytes”
- CEHS Kutscher Technology Innovation Grant “Thin Layer Chromatography - old methodology perfect for new students”
2023
- Layman Award 2023-2024 “The effect of LPCAT3 activation on cardiomyocyte metabolism during acute lipotoxicity”
- NPOD Project Leader 2022 “The role of LPCAT3 in pathogenesis of diabetic cardiomyopathy”
2022
- NPOD Program Seed Grant, September 2022, "The impact of obesity on satellite cells action in the skeletal muscle"
2020
- Vanderbilt Diabetes Center Discovery Program Grant, "In vivo 2H/13C flux analysis to assess LXR activation as a strategy to inhibit NASH pathogenesis"
2015
- National Science Centre in Poland PRELUDIUM 8 Grant, "Role of stearoyl-CoA desaturase 1 (SCD1) in regulation of adipose triglyceride lipase (ATGL) and lipolysis in cardiomyocytes"