TY - JOUR AU - Teratani, Toshiaki AU - Tomita, Kengo AU - Suzuki, Takahiro AU - Furuhashi, Hirotaka AU - Irie, Rie AU - Nishikawa, Makoto AU - Yamamoto, Junji AU - Hibi, Toshifumi AU - Miura, Soichiro AU - Minamino, Tohru AU - Oike, Yuichi AU - Hokari, Ryota AU - Kanai, Takanori T1 - Aortic carboxypeptidase–like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis PY - 2018/04/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI92863 VL - 128 IS - 4 UR - https://doi.org/10.1172/JCI92863 SP - 1581 EP - 1596 PB - The American Society for Clinical Investigation ER -