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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1581-1596
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number4
DOIs
Publication statusPublished - 2018 Apr 2

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Carboxypeptidases
Ligands
Hepatic Stellate Cells
Proteins
Liver
Obesity
Non-alcoholic Fatty Liver Disease
Pathology
Protein Deficiency
Peroxisome Proliferator-Activated Receptors
LDL Receptors
Fatty Liver
Liver Diseases
Fibrosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis. / Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Nishikawa, Makoto; Yamamoto, Junji; Hibi, Toshifumi; Miura, Soichiro; Minamino, Tohru; Oike, Yuichi; Hokari, Ryota; Kanai, Takanori.

In: Journal of Clinical Investigation, Vol. 128, No. 4, 02.04.2018, p. 1581-1596.

Research output: Contribution to journalArticle

Teratani, T, Tomita, K, Suzuki, T, Furuhashi, H, Irie, R, Nishikawa, M, Yamamoto, J, Hibi, T, Miura, S, Minamino, T, Oike, Y, Hokari, R & Kanai, T 2018, 'Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis', Journal of Clinical Investigation, vol. 128, no. 4, pp. 1581-1596. https://doi.org/10.1172/JCI92863
Teratani T, Tomita K, Suzuki T, Furuhashi H, Irie R, Nishikawa M et al. Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis. Journal of Clinical Investigation. 2018 Apr 2;128(4):1581-1596. https://doi.org/10.1172/JCI92863
Teratani, Toshiaki ; Tomita, Kengo ; Suzuki, Takahiro ; Furuhashi, Hirotaka ; Irie, Rie ; Nishikawa, Makoto ; Yamamoto, Junji ; Hibi, Toshifumi ; Miura, Soichiro ; Minamino, Tohru ; Oike, Yuichi ; Hokari, Ryota ; Kanai, Takanori. / Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 4. pp. 1581-1596.
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