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

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

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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 6

ACLP is a ligand that binds specifically to FZD8 and LRP6 receptors to form a ternary complex.

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ACLP is a ligand that binds specifically to FZD8 and LRP6 receptors to f...
(A) Combinations of ACLP-DDK and either human IgG, FZD8CRD-IgG, or LRP6N-IgG expression vectors (all 200 ng/well) were transfected into HEK293 cells followed by culture for 72 hours. Cell lysates were used for immunoprecipitation. TCL, total cell lysates. (B) Combinations of rACLP-DDK and either FZD8CRD-IgG, LRP6N-IgG, or IgG were mixed to be used for immunoprecipitation. (C) Combinations of rACLP-DDK, FZD8CRD-His, LRP6N-IgG, and IgG were mixed to be used for immunoprecipitation. (D) Binding curve and Scatchard plot of binding between murine ACLP and murine FZD8/Fc (upper left panel and upper right panel, respectively); and binding curve and Scatchard plot of binding between murine WNT3A and murine FZD8/Fc (lower left panel and lower right panel, respectively). The experiments were repeated 3 times.
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