Project Summary/Abstract
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. RELEVANCE: 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.