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, unhealthy diet rich in fructose, trans-unsaturated fatty acids and cholesterol, physical inactivity, high blood pressure, and diabetes.
Diabetic cardiomyopathy (DC) is characterized by abnormal cardiac structure and function in the absence of other cardiac risk factors and is often undiagnosed in patients with type 2 diabetes. Untreated, this condition increases the chance of heart failure at least 2.4-fold in men and 5.1-fold in women compared to individuals without diabetes.
Despite the increase in the number of cases in the past several decades, the underlying molecular mechanisms of DC pathogenesis remain poorly understood, thereby preventing the development of effective diagnostic tools and pharmacotherapies as well as preventive strategies.
The long-term goal of the Bednarski Lab is to identify metabolic processes that control the progression of DC so that these pathways 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 DC pathogenesis. In addition to in vitro experiments with primary cardiomyocytes and cell lines, we also use mice with cardiac-specific metabolic gene alterations. The in vivo studies involve implementation of the newly developed 13C metabolic flux analysis (MFA) technique, allowing for integrated multitissue 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 MS. 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.
Specific objectives of the Bednarski lab are:
- Assessing the role of aberrant polyunsaturated fatty acid metabolism in development of diabetic cardiomyopathy. The working hypothesis is that restoration of proper membrane composition will result in the mitigation of cardiometabolic stress and heart dysfunction.
- Identification of 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.
- Assessing the role of pyruvate metabolism in the development of diabetic cardiomyopathy. The working hypothesis is that alterations in pyruvate metabolism will contribute to balancing redox state and alleviating oxidative stress leading to improvement of cardiac function during diabetes.
Our central hypothesis is that identifying and targeting metabolic processes connected with aberrant lipid metabolism will result in the alleviation of lipotoxic effects and the mitigation of cardiac dysfunction. We expect to uncover druggable nodes that can be modulated in vivo with low risk of side effects.
Tomasz Bednarski, Assistant Professor
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 MFA and metabolomics profiling to identify liver phenotypes that accelerate the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), 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 fluxomics analysis. This newly developed, powerful tool allows for whole-body assessment of impaired metabolic fluxes leading to a better understanding of metabolic disorders. Additionally, I was actively participating in the review process of articles for journals specializing in diabetes, hepatology, and lipid metabolism. In addition to my research, I contributed to enhancing the success of students through service and mentoring.
|Adam Olichwier, Postdoctoral Fellow|
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
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
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
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
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
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
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
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
NPOD Program Seed Grant RFA, September 2022, "The impact of obesity on satellite cells action in the skeletal muscle"
UNL Start-up Grant
Vanderbilt Diabetes Center Discovery Program Grant, "In vivo 2H/13C flux analysis to assess LXR activation as a strategy to inhibit NASH pathogenesis"
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"