Our lab has a long standing interest in the mechanisms leading to the state of chronic, low-grade inflammation, which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to Interleukin 12 (IL-12), a major mediator of systemic inflammation, is augmented during aging leading to excessive production of IGFBP1, a protein that is secreted by the liver, binds to the Insulin-like Growth Factor 1 (IGF1), and neutralizes its bioactivity. Hepatic IL-12 hyperresponsiveness is caused by the intrinsic activation of an evolutionary conserved cellular stress response pathway involving neutral sphingomyelinase and its product, ceramide. Here we hypothesize that this IL-12 hyperresponsiveness impairs the insulin signaling pathway in liver. First, we will investigate how aging-associated IL-12 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades PI3K, Akt-1, and Foxo1 (for insulin), and ceramide, IRAK-1 and JNK (for IL-12). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young, aged and aged calorie restricted rats will be used. The regulation of IGFBP1 mRNA transcription by the two pathways will be investigated. These molecular studies will be complemented by assays of insulin- and IGFBP1-dependent functions in vivo, which include tests of IGF1 bioactivity, muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer. These studies may help to elucidate the cellular and molecular pathways responsible for muscle waste, frailty, and glucose dysregulation in the elderly. They may also reveal a novel mechanism for integration of inflammatory and metabolic signaling pathways and how aging affects these interactions. )

Public Health Relevance

Understanding the mechanisms that dysregulate liver functions during aging is very important for improving the health of older Americans, because liver plays critical role in many functions, including glucose homeostasis, innate immune response, drug metabolism etc.).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Hanaoka, Beatriz Y; Ormseth, Michelle J; Michael Stein, C et al. (2018) Secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis. Clin Rheumatol 37:1395-1399
Deevska, Gergana M; Dotson 2nd, Patrick P; Karakashian, Alexander A et al. (2017) Novel Interconnections in Lipid Metabolism Revealed by Overexpression of Sphingomyelin Synthase-1. J Biol Chem 292:5110-5122
Nolan, Michael W; Gieger, Tracy L; Karakashian, Alexander A et al. (2017) Outcomes of Spatially Fractionated Radiotherapy (GRID) for Bulky Soft Tissue Sarcomas in a Large Animal Model. Technol Cancer Res Treat 16:357-365
Shi, L; Banerjee, D; Dobierzewska, A et al. (2016) Direct regulation of IGF-binding protein 1 promoter by interleukin-1? via an insulin- and FoxO-1-independent mechanism. Am J Physiol Endocrinol Metab 310:E612-E623
Zhang, L P; Kline 4th, R H; Deevska, G et al. (2015) Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity. Neuroscience 311:166-79
Dotson 2nd, P Patrick; Karakashian, Alexander A; Nikolova-Karakashian, Mariana N (2015) Neutral sphingomyelinase-2 is a redox sensitive enzyme: role of catalytic cysteine residues in regulation of enzymatic activity through changes in oligomeric state. Biochem J 465:371-82
Empinado, Hyacinth M; Deevska, Gergana M; Nikolova-Karakashian, Mariana et al. (2014) Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content. Eur J Heart Fail 16:519-25
Moylan, Jennifer S; Smith, Jeffrey D; Wolf Horrell, Erin M et al. (2014) Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle. Redox Biol 2:910-20
Momchilova, Albena; Petkova, Diana; Staneva, Galya et al. (2014) Resveratrol alters the lipid composition, metabolism and peroxide level in senescent rat hepatocytes. Chem Biol Interact 207:74-80
Deevska, Gergana; Sunkara, Manjula; Karakashian, Claudia et al. (2014) Effect of procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3. J Lipid Res 55:2041-52

Showing the most recent 10 out of 25 publications