Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis
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
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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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 7

Activation of the canonical WNT pathway by ACLP activates HSCs through suppression of PPARγ signaling.

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Activation of the canonical WNT pathway by ACLP activates HSCs through s...
(A) Western blot of nuclear β-catenin and PPARγ in Aclpfl/fl and AclpHSC-KO HSCs treated with rACLP (100 ng/ml) or PBS for 10 hours in the presence or absence of DKK-1 (20 ng/ml). Lamin A/C was used as a loading control for nuclear protein. The experiments were repeated 3 times. (B) (Left panel) PPARγ promoter activity and (right panel) quantification of Pparg1 mRNA expression in AclpHSC-KO HSCs treated with rACLP (100 ng/ml) (n = 7/group) or PBS (n = 5/group) for 12 hours in the presence or absence of DKK-1 (20 ng/ml), FZD8CRD (20 μg/ml), and anti-ACLP antibody (10 μg /ml). (C) Quantification of Col1a1, Col1α2, and Acta2 mRNA in AclpHSC-KO HSCs treated with rACLP (100 ng/ml) (n = 7/group) or PBS (n = 5/group) for 10 hours in the presence or absence of DKK-1 (20 ng/ml), FZD8CRD (20 μg /ml), and anti-ACLP antibody (10 μg /ml). **P < 0.01 vs. AclpHSC-KO HSCs treated with PBS. (D) Quantification of Col1a1, Col1α2, and Acta2 mRNA in AclpHSC-KO HSCs treated with rACLP (100 ng/ml) (n = 7/group) or PBS (n = 5/group) for 12 hours in the presence of PPARγ siRNA or control siRNA. **P < 0.01 vs. AclpHSC-KO HSCs treated with PBS in the presence of control siRNA. (E) (Left panel) PPARγ promoter activity and (right panel) quantification of Pparg1 mRNA expression in Aclpfl/fl HSCs treated with ACLP siRNA (n = 7/group) or control siRNA (n = 5/group). (F) Quantification of Col1a1, Col1α2, and Acta2 mRNA in Aclpfl/fl HSCs treated with ACLP siRNA (n = 7/group) or control siRNA (n = 5/group) in the presence of PPARγ siRNA or control siRNA. **P < 0.01 vs. Aclpfl/fl HSCs treated with control siRNA. P values obtained via 1-way ANOVA with Tukey’s post hoc test (B–D, and F) and unpaired Student’s t tests (E). Data are shown as SEM.