The purpose of this proposal is to understand the liver-adipose tissue cross-talk pathway protective effects that the newly discovered protein, C1q TNF Related Protein 3 (CTRP3), has on the liver. Background: CTRP3 is a member of a family of adipose-tissue derived secreted proteins that exert a multitude of biological effects throughout the body. Our preliminary work demonstrates that elevated CTRP3 levels reduce diet-induced liver fat accumulation, also known as nonalcoholic fatty liver disease (NAFLD). Clinically, NAFLD is defined as the excessive accumulation of fat in the liver, usually due to obesity. NAFLD can progress to nonalcoholic steatohepatitis (NASH), or fatty liver plus inflammation and liver damage. Currently, there are no known pharmacological treatments available to treat NAFLD/NASH, and the effects of CTRP3 on NASH have not been examined. Fibroblast growth factor 21 (FGF21) is a secreted protein from the liver which, when FGF21 is absent there is a higher prevalence of NAFLD/NASH. Further, our pilot data shows that FGF21 can increase circulating CTRP3 levels, indicating a potential liver-adipose tissue crosstalk pathway. Conversely, FGF21 levels are elevated and CTRP3 levels are suppressed with obesity and NAFLD, indicating an obesity-induced FGF21 resistance, which implicates FGF21 resistance as a contributor to NAFLD/NASH. Our working hypothesis is that FGF21-CTRP3 represents a novel liver- adipose tissue signaling pathway that conspire to protect the liver from excessive fat accumulation. Further, we propose that disruptions to this pathway contribute to the development of NASH.
SPECIFIC AIMS : The three specific aims proposed to test this hypothesis are to: 1) to identify the specific signaling pathways in hepatocytes that confer CTRP3-induced increases to lipid metabolism and tolerance to lipid- induced stress, 2) establish that disruptions to the FGF21-CTRP3 crosstalk pathway promote NAFLD/NASH, and to 3) is to establish the relationship between circulating CTRP3 levels and NAFLD/NASH. RESEARCH DESIGN: 1) We will use cell culture and animal models of NASH with or with CTRP3 to establish the CTRP3- induced protective signaling pathways. 2) We will use cell culture and animal models (FGF21 knock out mice and FGF21 recombinant protein injections) to elucidate the FGF21-CTRP3 regulation pathway and understand the mechanisms by which obesity disrupts this pathway. 3) We will establish the relationship between CTRP3, FGF21, and other cytokines in both animal models and a clinical population of NAFLD/NASH.
The identification CTRP3-induced cellular signaling pathways and endogenous regulation are important prerequisites for the development of small molecule drug candidates that exert effects beneficial to human health. AREA GRANT JUSTIFICATION: With the upsides and limitations of undergraduate research in mind, the experimental plan is designed in discrete units that are amenable to the participation of multiple undergraduate students. Fundamentally, undergraduate students will be trained in a specific research technique and then tasked with using that technique to examine a specific cellular process. The investigators have a successful history incorporated a number of undergraduate and graduate students in research projects leading to national scientific presentations, Honors theses, and peer-reviewed publications.