The long-term objectives of this project are to determine the contribution of cholangiocyte lipoapoptosis to non-alcoholic fatty liver disease (NAFLD). Free fatty acid-induced apoptosis in the liver is a recognized aspect of hepatocyte injury;however cholangiocyte apoptosis has not been examined. This project will investigate cholangiocyte lipoapoptosis in NAFLD with an initial goal to determine critical apoptosis pathways and protective strategies. Preliminary data demonstrate that free fatty acids induced expression of proapoptotic miR-34a, c-Jun N-terminal kinase (JNK), and apoptosis in cultured cholangiocytes, and that signaling by palmitoleate prevented lipoapoptosis. The central hypothesis is that toxic free fatty acids contribute to biliary injury in NAFLD via proapoptotic microRNAs and the dietary molecule palmitoleate is protective against biliary lipoapoptosis.
The specific aims are to: (1) elucidate lipoapoptosis signaling in cholangiocytes regulated at the mitochondrial level and mitigated by palmitoleate;(2) identify the signaling pathway by which free fatty acids activate miR-34a;and (3) demonstrate cholangiocyte lipoapoptosis in clinically relevant liver disease and link this with proapoptotic microRNA signaling. A model of high-fat diet-induced obesity and liver steatosis will be employed, as well as liver samples from patients with NAFLD. Protection by dietary palmitoleate or genetic deficiency of miR-34a in the mouse will be tested. Completion of these aims will demonstrate the role of cholangiocyte lipoapoptosis and miR-34a in fatty liver injury, providing an opportunity to target this microRNA in human disease. Thus, this project has strong health relatedness by focusing on the clinically relevant cell death pathways present in the liver of patients. The project is closely related to the focus of the proposed Center, which is the discovery of signaling pathways through which nutrients and bioactive food compounds prevent, ameliorate, and treat obesity-related diseases, particulariy cardiovascular disease, diabetes, and NAFLD. Through advanced molecular, biochemical, and cell biological approaches to manipulate lipoapoptosis and miR-34a, this study will provide a foundation for a new line of inquiry in fatty liver injury to define the role of biliary cell death in disease.

Public Health Relevance

With the increase in obesity and metabolic syndrome in recent years, fatty liver injury is a growing health concern that in severe cases can lead to cirrhosis and liver failure. This project will study how cell death in bile duct epithelial cells contributes to non-alcoholic fatty liver disease. Successful completion of this project will define a role for these cells in fatty liver injury and may lead to new directions in therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM104320-01A1
Application #
8662973
Study Section
Special Emphasis Panel (ZGM1-TWD-C (C1))
Project Start
Project End
Budget Start
2014-08-05
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$238,500
Indirect Cost
$12,750
Name
University of Nebraska Lincoln
Department
Type
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68583
Kim, Jiyoung; Okla, Meshail; Erickson, Anjeza et al. (2016) Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378. J Biol Chem 291:20551-62
Wang, Hai; Zhao, Miaoyun; Sud, Neetu et al. (2016) Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis. Sci Rep 6:32246
Lu, Sizhao; Natarajan, Sathish Kumar; Mott, Justin L et al. (2016) Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway. PLoS One 11:e0147474
Farris, Eric; Brown, Deborah M; Ramer-Tait, Amanda E et al. (2016) Micro- and nanoparticulates for DNA vaccine delivery. Exp Biol Med (Maywood) 241:919-29
Krumbeck, Janina A; Maldonado-Gomez, Maria X; Ramer-Tait, Amanda E et al. (2016) Prebiotics and synbiotics: dietary strategies for improving gut health. Curr Opin Gastroenterol 32:110-9
Cordonier, Elizabeth L; Jarecke, Sarah K; Hollinger, Frances E et al. (2016) Inhibition of acetyl-CoA carboxylases by soraphen A prevents lipid accumulation and adipocyte differentiation in 3T3-L1 cells. Eur J Pharmacol 780:202-8
Yang, Junyi; Bindels, Laure B; Segura Munoz, Rafael R et al. (2016) Disparate Metabolic Responses in Mice Fed a High-Fat Diet Supplemented with Maize-Derived Non-Digestible Feruloylated Oligo- and Polysaccharides Are Linked to Changes in the Gut Microbiota. PLoS One 11:e0146144
Xie, Fang; Anderson, Christopher L; Timme, Kelsey R et al. (2016) Obesity-Dependent Increases in Oocyte mRNAs Are Associated With Increases in Proinflammatory Signaling and Gut Microbial Abundance of Lachnospiraceae in Female Mice. Endocrinology 157:1630-43
Natarajan, Sathish Kumar; Rasineni, Karuna; Ganesan, Murali et al. (2015) Structure, function and metabolism of hepatic and adipose tissue lipid droplets: implications in alcoholic liver disease. Curr Mol Pharmacol :
Shu, Jiang; Chiang, Kevin; Zempleni, Janos et al. (2015) Computational Characterization of Exogenous MicroRNAs that Can Be Transferred into Human Circulation. PLoS One 10:e0140587

Showing the most recent 10 out of 24 publications