The Role of Protease Activated Receptor 2 (PAR2) in the Development of Metabolically Induced Liver Pathology and Fibro-Inflammatory Processes
Shearer, Andrew.
2019
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Nonalcoholic Fatty
Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) are related liver
pathologies whose prevalence has increased in recent decades due to over nutrition and
widespread adoption of a sedentary lifestyle. Protease-activated receptor-2 (PAR2) is a
member of the PAR-family of G protein coupled receptors that are activated by
extracellular serine proteases. This thesis ... read morefocuses on the role of PAR2 in the
development of NAFLD and NASH and seeks to understand the mechanisms by which PAR2
influences their development. Both NAFLD and NASH result from unhealthy lifestyle and
are generally comorbid with: obesity, diabetes, and cardiovascular disease.
Additionally, NASH and NAFLD share a common etiology and are generally accepted as
existing on a pathological spectrum. NAFLD is assumed to be relatively benign while the
development of NASH presages cirrhosis and hepatocellular carcinoma. PAR2 represents a
novel point for therapeutic intervention in NAFLD and NASH as PAR2 has been implicated
in hepatocellular dysfunction, fibroblast activation, and inflammatory cell recruitment.
The broad range of roles played by PAR2 in disease progression and its effects on so
many varied cell types implies that PAR2 is an important mediator in the development and
progression of NAFLD and NASH. Using PZ-235, a cell-penetrating pepducin, we show that
inhibiting PAR2 reduces the metabolic and inflammatory pathologies that stem from a
methionine choline deficient diet. We further show that PZ-235 inhibits PAR2-mediated
activation of stellate cells to myofibroblasts in vitro and inhibits their activation
and the development of fibrosis caused by carbon tetrachloride. Unexpectedly, we
observed that treatment with PZ-235 also appears to reduce the level of hepatocellular
necrosis associated with carbon tetrachloride challenge. Additionally, we show through
the use of multiple mouse models of diabetes and obesity that PAR2 appears to be a
critical factor in the development of hepatic insulin resistance, a crucial step in the
development of NASH. We further demonstrate that PAR2-mediated insulin resistance is
most likely a result of increased PAR2-triggered increases in intracellular calcium.
Finally, we show that treatment of diabetic animals with PZ-235 partially restores
hepatic insulin sensitivity and reduces total glucose exposure. In aggregate this work
shows that PAR2-signaling is a critical component and viable point of therapeutic
intervention in the development of liver
pathology.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Biochemistry.
Advisor: Athan Kuliopulos.
Committee: Lidija Covic, Laura Liscum, Phil Hinds, and Mikel Garcia-Markos.
Keywords: Biochemistry, and Pharmacology.read less - ID:
- 41687w952
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