studies

514A AASLD ABSTRACTS HEPATOLOGY, October, 2015
614
Increased expression of ORM1-like protein 3 (ORMDL3)
in biliary epithelial cells may be related to the pathogenesis
of primary biliary cirrhosis
Motoko Sasaki 1 , Yasunori Sato 1 , Yasuni Nakanuma 2,1 ; 1 Human
Pathology, Kanazawa University Graduate School of Medicine,
Kanazawa, Japan; 2 Shizuoka Cancer Center, Shizuoka, Japan
Background/Aims: ORM1-like protein 3 (ORMDL3) localizes
to the endoplasmic reticulum (ER), mediates calcium homeostasis
and facilitates the unfolded-protein response, which is
related to the endogenous induction of inflammation. ORMDL3
gene is located in chromosome 17q12-q21region, which is
one of candidates associated with the development of primary
biliary cirrhosis (PBC), asthma and Crohn’s disease. Although
upregulated expression of ORMDL3 was reported in airway
epithelial cells in asthma, the expression of ORMDL3 in biliary
epithelial cells (BECs) in PBC and other liver diseases has not
been reported, so far. We hypothesized that altered expression
of ORMDL3 in BECs in PBC may be related to the deregulated
autophagy and abnormal expression of mitochondria
antibodies specifically seen in PBC. Methods: We examined
immunohistochemically the expression of ORMDL3 in BECs in
livers taken from patients with PBC (n=50), control diseased
livers (n=55), such as primary sclerosing cholangitis (PSC),
and normal livers (n=20). The association between the expression
of ORMDL3 and the expression of mitochondrial antigen
PDC-E2, autophagy-related markers (LC3, p62) or senescent
markers (p16 INK4a and p21 WAF1/Cip1 ) was also examined. In
addition, a correlation between the extent of biliary expression
of ORMDL3 and the extent of ORMDL3-positive inflammatory
cells infiltration in small bile ducts was evaluated. Furthermore,
we examined the expression of ORMDL3 at mRNA level in cultured
BECs treated with various cytokines (IL-4 [10ng/ml]; IL-13
[10ng/ml]; IFN-γ [1000U/ml], TNF-α [10ng/ml] and TGF-β
[4ng/ml]) and a protein kinase A activator, forskolin (5 mM).
Results: The expression of ORMDL3 was seen in the cytoplasm
and apical surface in damaged small bile ducts (SBDs) in PBC.
The expression of ORMDL3 was significantly more extensive
in SBDs in PBC, especially in early stage PBC, compared with
control diseased livers and normal livers (p