Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis
Toshiaki Teratani, … , Ryota Hokari, Takanori Kanai
Toshiaki Teratani, … , Ryota Hokari, Takanori Kanai
Published April 2, 2018; First published March 19, 2018
Citation Information: J Clin Invest. 2018;128(4):1581-1596. https://doi.org/10.1172/JCI92863.
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Categories: Research Article Cell biology Hepatology

Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis

Abstract

Incidence of nonalcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of metabolic syndrome, has been increasing worldwide with the rise in obesity; however, its pathological mechanism is poorly understood. Here, we demonstrate that the hepatic expression of aortic carboxypeptidase–like protein (ACLP), a glycosylated, secreted protein, increases in NASH in humans and mice. Furthermore, we elucidate that ACLP is a ligand, unrelated to WNT proteins, that activates the canonical WNT pathway and exacerbates NASH pathology. In the liver, ACLP is specifically expressed in hepatic stellate cells (HSCs). As fatty liver disease progresses, ACLP expression is enhanced via activation of STAT3 signaling by obesity-related factors in serum. ACLP specifically binds to frizzled-8 and low-density lipoprotein–related receptor 6 to form a ternary complex that activates canonical WNT signaling. Consequently, ACLP activates HSCs by inhibiting PPARγ signals. HSC-specific ACLP deficiency inhibits fibrosis progression in NASH by inhibiting canonical WNT signaling in HSCs. The present study elucidates the role of canonical WNT pathway activation by ACLP in NASH pathology, indicating that NASH can be treated by targeting ACLP-induced canonical WNT pathway activation in HSCs.

Authors

Toshiaki Teratani, Kengo Tomita, Takahiro Suzuki, Hirotaka Furuhashi, Rie Irie, Makoto Nishikawa, Junji Yamamoto, Toshifumi Hibi, Soichiro Miura, Tohru Minamino, Yuichi Oike, Ryota Hokari, Takanori Kanai

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Figure 4

ACLP activates the canonical WNT pathway in HSCs in an FZD8/LRP6-dependent manner, thus promoting HSC activation.

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ACLP activates the canonical WNT pathway in HSCs in an FZD8/LRP6-depende...
(A) (Left panel) Western blot for p-LRP6, LRP6, and β-catenin and (right panels) quantification of Axin2, Myc, Ccnd1, Col1a1, Col1α2, and Acta2 mRNA in AclpHSC-KO HSCs treated with rACLP (100 ng/ml) or PBS for 12 hours (n = 5/group). **P < 0.01 vs. AclpHSC-KO HSCs treated with PBS. (B) (Left panel) Western blot for and quantification of p-LRP6, LRP6, and β-catenin, and (right panels) quantification of Axin2, Myc, Ccnd1 Col1a1, Col1α2, and Acta2 mRNA in Aclpfl/fl HSCs treated with ACLP or control siRNA for 72 hours (n = 5/group). **P < 0.01 vs. Aclpfl/fl HSCs treated with control siRNA. (C) (Left panel) Western blot of p-LRP6, LRP6, and β-catenin, and (right panel) quantification of Axin2, Myc, Ccnd1 Col1a1, Col1α2, and Acta2 mRNA in AclpHSC-KO HSCs treated with rACLP (100 ng/ml) for 12 hours in the presence of LRP6 siRNA, FZD1 siRNA, FZD3 siRNA, FZD6 siRNA, FZD8 siRNA, or control siRNA (n = 5/group). **P < 0.01 vs. AclpHSC-KO HSCs treated with PBS in the presence of control siRNA. P values obtained via 1-way ANOVA with Tukey’s post hoc test (C), unpaired Student’s t tests (A and B, right panels), and Mann-Whitney U test (B, left panel). Data are shown as SEM.