Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
J Hepatol. 2014 Jul;61(1):98-106. doi: 10.1016/j.jhep.2014.03.018. Epub 2014 Mar 18.
BACKGROUND & AIMS: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis.
ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4)(-/-)ACAT1(+/+) and TLR4(-/-)ACAT1(-/-) mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis.
ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling.
ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.
酰基辅酶 A：胆固醇酰基转移酶（ACAT）催化游离胆固醇（FC）向胆固醇酯的转化，从而防止 FC 的过度积累。我们最近发现，肝星状细胞（HSCs）中 FC 的积累在肝纤维化的进展中起作用，但 ACAT1 对肝纤维化的影响尚未阐明。在本研究中，我们旨在确定 ACAT1 在肝纤维化发病机制中的作用。
ACAT1 缺陷型和野生型小鼠，或 Toll 样受体 4（TLR4）（-/-）ACAT1（+/+）和 TLR4（-/-）ACAT1（-/-）小鼠接受胆管结扎（BDL）3 周或接受四氯化碳（CCl4）4 周，以诱导肝纤维化。
ACAT1 是小鼠和人原代 HSCs 的主要同工酶，ACAT2 是小鼠原代肝细胞和枯否细胞的主要同工酶。ACAT1 缺陷显著加重了小鼠肝纤维化模型中的肝纤维化，而不影响肝细胞损伤或肝炎症的程度，包括肝细胞凋亡或枯否细胞激活。ACAT1 缺陷显著增加了 HSCs 中的 FC 水平，增加了 TLR4 蛋白的表达，下调了转化生长因子-β（TGFβ）假受体 Bamb（骨形态发生蛋白和激活素膜结合抑制剂）的表达，导致 HSCs 对 TGFβ 激活的敏感性增加。ACAT1 缺陷加重肝纤维化依赖于 FC 积累诱导的 TLR4 信号增强。
ACAT1 缺陷主要通过增强 HSCs 中的 FC 积累来加重肝纤维化。调节 HSCs 中的 ACAT1 活性可能是治疗肝纤维化的一个靶点。
