TY - JOUR
T1 - Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells
AU - Teratani, Toshiaki
AU - Tomita, Kengo
AU - Wada, Akinori
AU - Sugihara, Nao
AU - Higashiyama, Masaaki
AU - Inaba, Kenichi
AU - Horiuchi, Kazuki
AU - Hanawa, Yoshinori
AU - Nishii, Shin
AU - Mizoguchi, Akinori
AU - Tanemoto, Rina
AU - Ito, Suguru
AU - Okada, Yoshikiyo
AU - Kurihara, Chie
AU - Akita, Yoshihiro
AU - Narimatsu, Kazuyuki
AU - Watanabe, Chikako
AU - Komoto, Shunsuke
AU - Oike, Yuichi
AU - Miura, Soichiro
AU - Hokari, Ryota
AU - Kanai, Takanori
N1 - Funding Information:
We thank Dr. Gou Young Koh (Korea Advanced Institute of Science and Technology) and Dr. Andras Nagy (University of Toronto) for the generous gift of Angptl4 mice and Dr. Kunio Yasunaga (Astellas Pharmaceutical Co. Ltd., Tsukuba, Japan) for helpful advice and technical support. This study was supported by grants from the Uehara Memorial Foundation, the National Defense Medical College, Keio University School of Medicine, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan. +/−
Funding Information:
We thank Dr. Gou Young Koh (Korea Advanced Institute of Science and Technology) and Dr. Andras Nagy (University of Toronto) for the generous gift of Angptl4+/− mice and Dr. Kunio Yasunaga (Astellas Pharmaceutical Co. Ltd., Tsukuba, Japan) for helpful advice and technical support. This study was supported by grants from the Uehara Memorial Foundation, the National Defense Medical College, Keio University School of Medicine, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Publisher Copyright:
© 2021 The Japan Society of Hepatology
PY - 2021/5
Y1 - 2021/5
N2 - Aim: We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Methods: Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. Results: In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-β-induced activation in vivo and in vitro. Conclusions: Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.
AB - Aim: We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Methods: Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. Results: In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-β-induced activation in vivo and in vitro. Conclusions: Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.
KW - BMP and activinmembrane-bound inhibitor
KW - angiopoietin-like protein 4
KW - free cholesterol
KW - hepatic stellate cell
KW - non-alcoholic steatohepatitis
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UR - http://www.scopus.com/inward/citedby.url?scp=85103618043&partnerID=8YFLogxK
U2 - 10.1111/hepr.13603
DO - 10.1111/hepr.13603
M3 - Article
AN - SCOPUS:85103618043
SN - 1386-6346
VL - 51
SP - 580
EP - 592
JO - Hepatology Research
JF - Hepatology Research
IS - 5
ER -
