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 2

HSC-specific ACLP deficiency inhibits progression of liver fibrosis in murine NASH.

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HSC-specific ACLP deficiency inhibits progression of liver fibrosis in m...
(A–C) 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 a control diet for 24 weeks (n = 6/group). (A) (Upper panels) Representative H&E-stained, MT-stained, and αSMA-immunostained liver samples. Scale bars: 100 μm (H&E-stained and MT-stained sections); 50 μm (αSMA-immunostained sections). (Lower panels) Quantification of MT staining and αSMA immunostaining. (B) Hepatic expression of Col1a1, Col1a2, Acta2, and Tgfb mRNA. (C) Serum ALT activities and hepatic TG levels. **P < 0.01 vs. Aclpfl/fl mice fed a control diet for 24 weeks. P values obtained via 1-way ANOVA with Tukey’s post hoc test. Data are shown as SEM.