Research Summary/Abstract Non-alcoholic fatty liver disease (NAFLD) is one of the leading
causes of chronic liver disease that can progress into a more advanced form- non-alcoholic
steatohepatitis (NASH) featuring inflammation and fibrosis. There is no specific medicine for
advanced NASH patients, making it critical to find supplements to mitigate liver damage. Non-
psychoactive cannabinoids cannabidiol (CBD) and cannabigerol (CBG) has shown anti-
inflammatory effect in other diseases, but their therapeutic effect in NAFLD/NASH is unknown.
The goal of this project is to evaluate the efficacy of CBG with or without CBD intervention to
reduce NAFLD/NASH. We have found that administration of CBG in diet-induced NAFLD/NASH
leads to decreases in hepatic steatosis, fibrosis, immune cell infiltration, and cytokine secretion in
the liver. Based on these data, we hypothesize that Cannabinoids attenuate immune cell
recruitment, suppresses inflammatory mediator release, and thus mitigate liver damage caused
by diet in mice. We propose three specific aims to address the hypothesis: (i) Evaluate the
administration of CBG with or without CBD in alleviating the symptoms of NAFLD and NASH,
specifically liver steatosis, inflammation, fibrosis, and oxidative stress, in two mouse models. (ii)
Assess the expansion of T cells and mast cells across immune compartments. (iii) Evaluate
crosstalk between PPARg activation and the TGF-β1 pathway in different cell populations in the
liver. C57BL/6 mice will receive special diets to develop NAFLD/NASH symptoms and then be
administered with CBG with or without the combination of CBD. The liver, peripheral blood, and
spleen will be examined for cellular and secreted indicators of inflammation. Cytokines, including
TGF-β1 and its pathway, will be evaluated in isolated hepatocytes, cholangiocytes and immune
cell subsets via total RNA sequencing, multiplex cytometry bead assay, and qRT-PCR. Further,
cannabinoid receptors and their downstream pathways will be evaluated with or without
cannabinoid treatment in vivo and in vitro. We predict CBG alone or with CBD will protect the liver
from NAFLD/NASH symptoms and inhibit immune cell infiltration into the liver via TGF-b1 involved
pathway and PPARg (CBG receptor) activation. This research will provide therapeutic efficacy
data about CBG and CBD for NAFLD/NASH for the first time in mice, which will benefit future
cannabinoid-related animal and human studies. Further, we will provide in-depth information
about molecular mechanisms in which CBG alone or with CBD diminishes NAFLD/NASH
progression. Through these aims, we will build a rigorous body of evidence about the effect of
cannabinoids during the pathogenesis of NAFLD/NASH.
