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
Autor: | Rina Tanemoto, Kazuyuki Narimatsu, Shunsuke Komoto, Takanori Kanai, Yuichi Oike, Toshiaki Teratani, Shin Nishii, Akinori Mizoguchi, Yoshikiyo Okada, Chie Kurihara, Kenichi Inaba, Soichiro Miura, Kengo Tomita, Suguru Ito, Kazuki Horiuchi, Ryota Hokari, Yoshinori Hanawa, Yoshihiro Akita, Akinori Wada, Chikako Watanabe, Nao Sugihara, Masaaki Higashiyama |
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Rok vydání: | 2020 |
Předmět: |
Lipoprotein lipase
Hepatology Angiogenesis Chemistry nutritional and metabolic diseases hemic and immune systems Inflammation Bone morphogenetic protein Pathogenesis 03 medical and health sciences 0302 clinical medicine Infectious Diseases ANGPTL4 030220 oncology & carcinogenesis Hepatic stellate cell Cancer research medicine 030211 gastroenterology & hepatology medicine.symptom Transforming growth factor |
Zdroj: | Hepatology research : the official journal of the Japan Society of HepatologyREFERENCES. 51(5) |
ISSN: | 1386-6346 |
Popis: | Aim We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in nonalcoholic 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 (MCD) 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. Angptl4 treatment reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-s) 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 may represent a novel therapeutic option for NASH. |
Databáze: | OpenAIRE |
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