Mariana Nikolova-Karakashian, PhD
Connect
859-323-8210mariana.karakashian@uky.edu
Positions
- Professor
- Director of Research, Department of Physiology
College Unit(s)
Other Affiliation(s)
- CVRC - Affiliated Faculty
- Markey Cancer Center - Affiliated Faculty
Biography and Education
Education
Ph.D. in Biochemistry and Biophysics . Institute of Biophysics, Bulgarian Academy of Science, Sofia, Bulgaria
M.Sci. in Theoretical nuclear physics. Specialization in physics of the nucleus and elementary particles, Faculty of Physics, Sofia University "St. Clement Ochridski" , Sofia, Bulgaria
Research
Sphingolipids are diverse class of lipid molecules that participate in regulation of various cell functions. Sphingomyelin is one of the main sphingolipids in mammalian cells and can be hydrolyzed to ceramide by a family of enzymes termed sphingomyelinases. Pro-inflammatory cytokines, oxidative stress, and aging control sphingomyelinase activity, thus generating quantities of ceramide, which in turn acts to regulate distinct down-stream targets resulting in a variety of cellular responses. Our lab uses state-of the art molecular and biochemical approach to understand the mechanisms that determines the activity of sphingomyelinases, specifically that of neutral sphingomyelinase-2 (smpd3), and to define new ceramide-dependent down-stream targets in the context of the IL-1b signaling pathway.
In addition to mediating signaling pathways, sphingolipids play a role in maintaining lipid homeostasis of the cells. Our ongoing study suggests that disruption of sphingolipid balance in the liver has strong influence on the partitioning of the fat into neutral lipids, the development of steatotic liver and respectively insulin resistance and hyperglycemia. Our goal is by combining classical in vitro/in vivo approach to decipher the coordinated regulation of sphingolipid, glycerophospholipid, and TAG metabolism and define new mechanisms that maintain sphingolipid homeostasis in cells.
Our long-term objective is to apply the results of our research towards better understanding the role of lipids in the onset of key liver pathologies associated with aging, including fatty liver and chronic inflammation
Techniques often used in the lab:
Biochemistry: Western blot, protein purification, co-immunoprecipitation; Real time and classical RT-PCR, gel-shift analyses, enzyme activity assays, lipid extractions, and lipid analysis by TLC, HPLC, and MasSpectrometry. Sub-cellular fractionation.
Molecular biology: Cloning and expresison of various genes of interest in bacterial and mammalian systems using plasmids or adenoviruses, site-directed mutagenesis.
Cell biology: Maintaining of different cell lines. Isolation of primary hepatocytes from rats and mice. Creation and work with stably transfected cell lines. Transient overexpression or silencing of proteins in mammalian cells by plasmid- or adenovirus-mediated gene transfer. Fluorescent microscopy of subcellular organelles. Indirect immunofluorescence.Receptor internalization and ligand-receptor interactions.
Work with small animals: Breeding of transgenic animals, genotyping, In vivo gene overexpression/silencing through adenoviral-mediated gene trasnfer, Mouse and rat modes of inflammation (LPS administration), diet-induced diabetes. Organ and tissue collection.
Selected Publications
2024: Quadri Z, Elsherbini A, Crivelli SM, El-Amouri SS, Tripathi P, Zhu Z, Ren X, Zhang L, Spassieva SD, Nikolova-Karakashian M, Bieberich E.J Extracell Vesicles. 2024 Jul;13(7):e12477. doi: 10.1002/jev2.12477.PMID: 38988257
2023: El-Amouri S, Karakashian A, Bieberich E, Nikolova-Karakashian M.J Lipid Res. 2023 Oct;64(10):100435. doi: 10.1016/j.jlr.2023.100435. Epub 2023 Aug 26.PMID: 37640282
2022: Araujo N, Sledziona J, Noothi SK, Burikhanov R, Hebbar N, Ganguly S, Shrestha-Bhattarai T, Zhu B, Katz WS, Zhang Y, Taylor BS, Liu J, Chen L, Weiss HL, He D, Wang C, Morris AJ, Cassis LA, Nikolova-Karakashian M, Nagareddy PR, Melander O, Evers BM, Kern PA, Rangnekar VM.Front Oncol. 2022 Mar 29;12:860446. doi: 10.3389/fonc.2022.860446. eCollection 2022.PMID: 35425699
2021: Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane. (2021) Deevska G, Dotson PP 2nd, Mitov M, Butterfield DA, Nikolova-Karakashian M. Cells. 10(6):1278.
2020: Nikolova-Karakashian M.Methods Mol Biol. 2021;2187:113-129. doi: 10.1007/978-1-0716-0814-2_7.PMID: 32770504
2020: Guo W, Wu D, Dao MC, Li L, Lewis ED, Ortega EF, Eom H, Thomas M, Nikolova-Karakashian M, Meydani M, Meydani SN.J Nutr. 2020 Nov 19;150(11):2950-2960. doi: 10.1093/jn/nxaa259.
2019: Sphingolipids at the Crossroads of NAFLD and Senescence.(2018)Nikolova-Karakashian M Adv Cancer Res. ;140:155-190.
2018: Zhong L, Kong JN, Dinkins MB, Leanhart S, Zhu Z, Spassieva SD, Qin H, Lin HP, Elsherbini A, Wang R, Jiang X, Nikolova-Karakashian M, Wang G, Bieberich E.J Lipid Res. 2018 May;59(5):795-804. doi: 10.1194/jlr.M080879. Epub 2018 Mar 22.PMID: 29567647
2016: Shi L, Banerjee D, Dobierzewska A, Sabapathi S, Karakashian A, Giltiay N, Nikolova-Karakashian MN. Am J Physiol Endocrinol Metab. (E-pub ahead of print).
2015: Neutral sphingomyelinase-2 is a redox sensitive enzyme: role of catalytic cysteine residues in regulation of enzymatic activity through changes in oligomeric state (2015) Dotson PP, Karakashian AA, Nikolova-Karakashian MN. Biochem J; 465(3):371-82.
2014: Effect of procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3 (2014). Deevska G, Sunkara M, Karakashian C, Peppers B, Morris AJ, Nikolova-Karakashian MN. J Lipid Res; 55(10):2041-52.
2012: Interleukin 1尾 Regulation of FoxO1 Protein Content and Localization: Evidence for a Novel Ceramide-dependent Mechanism (2012). Dobierzewska A, Shi L, Karakashian AA, Nikolova-Karakashian MN. J Biol Chem. 287(53):44749-60.
2012: Characterization of secretory sphingomyelinase activity, lipoprotein sphingolipid content and LDL aggregation in ldlr-/- mice fed on a high-fat diet (2012). Deevska GM, Sunkara M, Morris AJ, Nikolova-Karakashian MN. Biosci Rep. 32(5):479-90.
2011: Protein phosphatase 2A and neutral sphingomyelinase 2 regulate IRAK-1 Ubiquitination and degradation in response to IL-1{beta} (2011) Dobierzewska A, Giltiay NV, Sabapathi S, Karakashian AA, Nikolova-Karakashian MN. J Biol Chem. 2011 Jun 27. 286(37):32064-73
2010: Studies on the role of acid sphingomyelinase and ceramide in the regulation of tumor necrosis factor alpha - converting (TACE) enzyme activity and TNFa secretion in macrophages (2010). Rozenova KA, Deevska GM, Karakashian AA, Nikolova-Karakashian MN. J Biol Chem. 285(27):21103-13.
2009: Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice (2009) Deevska GM, Rozenova KA, Giltiay NV, Chambers MA, White J, Boyanovsky BB, Wei J, Daugherty A, Smart EJ, Reid MB, Merrill AH Jr, Nikolova-Karakashian M. J Biol Chem. ;284(13):8359-68.
2007: Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation (2007) Rutkute K, Asmis RH, Nikolova-Karakashian MN. J Lipid Res. 48(11):2443-52, 2007.
2007: Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2 (2007). Rutkute K, Karakashian AA, Giltiay NV, Dobierzewska A, Nikolova-Karakashian MN. Hepatology. 46(4):1166-1176
2005: Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1beta in hepatocytes (2005) Giltiay NV, Karakashian AA, Alimov AP, Ligthle S, Nikolova-Karakashian MN. J Lipid Res; 46(11):2497-505
2003: Uptake and metabolism of low density lipoproteins with elevated ceramide content by human microvascular endothelial cells: implications for the regulation of apoptosis. (2003) Boyanovsky B, Karakashian A, King K, Giltiay N, Nikolova-Karakashian M. J Biol Chem. ;278(29):26992-9.
2000: Activation of sphingolipid turnover and chronic generation of ceramide and sphingosine in liver during aging (2000). Lightle SA, Oakley JI, Nikolova-Karakashian MN. Mech Ageing Dev. ;120(1-3):111-25.
1999: Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase.(1999) Aug茅 N, Nikolova-Karakashian M, Carpentier S, Parthasarathy S, N猫gre-Salvayre A, Salvayre R, Merrill AH Jr, Levade T. J Biol Chem.;274(31):21533-8.
1997: Bimodal regulation of ceramidase by interleukin-1beta. Implications for the regulation of cytochrome p450 2C11. (1997) Nikolova-Karakashian M, Morgan ET, Alexander C, Liotta DC, Merrill AH Jr. J Biol Chem.;272(30):18718-24.
1992: Sphingomyelin-metabolizing enzymes and protein kinase C activity in liver plasma membranes of rats fed with cholesterol-supplemented diet (1992) Nikolova-Karakashian MN, Gavrilova NJ, Petkova DH, Setchenska MS. Biochem Cell Biol.;70(7):613-6.
1992: Influence of cholesterol on sphingomyelin metabolism and hemileaflet fluidity of rat liver plasma membranes (1992) Nikolova-Karakashian MN, Petkova H, Koumanov KS. Biochimie. 74(2):153-9.
1991: Influence of phospholipid environment on the phosphatidylethanolamine: ceramide-phosphoethanolamine transferase in rat liver plasma membranes (1991) Nikolova, M.N., Petkova, D.H., & Koumanov, K.S. Int. J. Biochem. 24: 447-453.
1989: Sphingomyelin and ceramide- phosphoethanolamine synthesis in ram spermatozoa plasma membranes (1989) Hinkovska-Galcheva, V.T., Petkova, D.H., & Nikolova, M.N. Int. J. Biochem. 21: 1153-1156.