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.
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.
|Okla, Meshail; Zaher, Walid; Alfayez, Musaad et al. (2018) Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1? on White Adipocyte Browning. Inflammation 41:626-642|
|Chakrabarti, Subhadeep; Guha, Snigdha; Majumder, Kaustav (2018) Food-Derived Bioactive Peptides in Human Health: Challenges and Opportunities. Nutrients 10:|
|Kittana, Hatem; Quintero-Villegas, Maria I; Bindels, Laure B et al. (2018) Galactooligosaccharide supplementation provides protection against Citrobacter rodentium-induced colitis without limiting pathogen burden. Microbiology 164:154-162|
|Neilsen, Beth K; Chakraborty, Binita; McCall, Jamie L et al. (2018) WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage. BMC Cancer 18:673|
|Kuss, Mitchell; Kim, Jiyoung; Qi, Dianjun et al. (2018) Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function. Acta Biomater 71:486-495|
|Yates, Dustin T; Petersen, Jessica L; Schmidt, Ty B et al. (2018) ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward-How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe. J Anim Sci 96:2987-3002|
|Natarajan, Sathish Kumar; Ibdah, Jamal A (2018) Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy. Int J Mol Sci 19:|
|Camara Teixeira, Daniel; Cordonier, Elizabeth L; Wijeratne, Subhashinee S K et al. (2018) A cell death assay for assessing the mitochondrial targeting of proteins. J Nutr Biochem 56:48-54|
|Hakguder, Zeynep; Shu, Jiang; Liao, Chunxiao et al. (2018) Genome-scale MicroRNA target prediction through clustering with Dirichlet process mixture model. BMC Genomics 19:658|
|McAtee, Caitlin O; Booth, Christine; Elowsky, Christian et al. (2018) Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling. Matrix Biol :|
Showing the most recent 10 out of 68 publications