MOLMET
873
S2212-8778(19)30698-2
10.1016/j.molmet.2019.08.019
The Authors
Original Article
PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease
Rajashree
Rana
1
Andrew M.
Shearer
1
2
Elizabeth K.
Fletcher
1
Nga
Nguyen
1
Srijoy
Guha
1
Daniel H.
Cox
2
Manal
Abdelmalek
3
Ying
Wang
3
James D.
Baleja
2
Lidija
Covic
1
2
Athan
Kuliopulos
1
2
∗
athan.kuliopulos@tufts.edu
1
Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
Center for Hemostasis and Thrombosis Research
Tufts Medical Center
800 Washington St
Boston
MA
02111
USA
Center for Hemostasis and Thrombosis Research, 800 Washington St, Tufts Medical Center, Boston, MA, 02111, USA
2
Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
Tufts University School of Graduate Biomedical Sciences
Tufts University School of Medicine
Boston
MA
02111
USA
Tufts University School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA
3
Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, 27710, USA
Division of Gastroenterology and Hepatology
Duke University Medical Center
Durham
NC
27710
USA
Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, 27710, USA
∗
Corresponding author. Center for Hemostasis and Thrombosis Research, Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.
Center for Hemostasis and Thrombosis Research
Tufts Medical Center
800 Washington St
Boston
MA
02111
USA
Abstract
Objective
Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD.
Methods
Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1−/−) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites.
Results
Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver.
Conclusions
These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions.
Highlights
•
Increases in cholesterol in NAFLD and NASH is a vexing problem.
•
PAR2 has been identified as a connecting hub between metabolism and fibrosis.
•
Severity of NAFLD and cholesterol correlate with hepatocyte PAR2 expression.
•
PAR2 suppresses reverse cholesterol transport and lipid breakdown in liver.
Keywords
Cholesterol
Energy metabolism
Fatty liver
Protease-activated receptor 2
NASH
Abbreviations
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
PAR2
Protease-Activated Receptor 2
JNK
c-Jun N-terminal kinase
NAS
NAFLD activity score
Fib
Fibrosis
KBJ00000000011542
2019-10-26T18:47:15
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