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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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 1

In the liver, ACLP is specifically expressed by HSCs, and its expression increases in both humans and mice as NAFLD progresses.

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In the liver, ACLP is specifically expressed by HSCs, and its expression...
(A) (Left panels) Representative immunofluorescence double-staining images of ACLP (red) and GFAP (green) in human liver tissue samples from controls (n = 14), NAFL patients (n = 16), and NASH patients (n = 44). Costained sites are shown in yellow. The nuclei were stained with DAPI (blue). Scale bars: 100 μm. Single-channel images are shown in Supplemental Figure 1. (Right panels) Quantification of ACLP/GFAP double-positive cells, ACLP staining, and mRNA expression. **P < 0.01; *P < 0.05 vs. control (normal) liver samples. (B–D) Eight-week-old male Aclpfl/fl and AclpHSC-KO mice were fed an HFC diet for 4 weeks (n = 6/group) or 24 weeks (n = 9/group), or fed a control diet (CE-2) for 24 weeks (n = 6/group). (B) (Left panel) Hepatic Aclp mRNA expression levels. (Middle panel) Western blot for and quantification of hepatic ACLP expression in Aclpfl/fl mice. **P < 0.01 vs. Aclpfl/fl mice fed the control diet. (Right panel) Western blot for hepatic ACLP expression in Aclpfl/fl mice and AclpHSC-KO mice. (C) Representative images of immunofluorescence double-staining of ACLP (red) and GFAP (green), with costained sites shown in yellow. The nuclei were stained with DAPI (blue). Scale bars: 100 μm. Single-channel images are shown in Supplemental Figure 4. (D) (Left panel) Western blot for and quantification of ACLP expression in HSCs in Aclpfl/fl mice. **P < 0.01 vs. HSCs in Aclpfl/fl mice fed the control diet. (Right panel) Western blot for ACLP expression in HSCs in Aclpfl/fl mice and AclpHSC-KO mice. P values obtained via 1-way ANOVA with Tukey’s post hoc test. Data are shown as SEM.