Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Gastroenterology. 2012 Jan;142(1):152-164.e10. doi: 10.1053/j.gastro.2011.09.049. Epub 2011 Oct 10.
BACKGROUND & AIMS: Some studies have indicated that dietary cholesterol has a role in the progression of liver fibrosis. We investigated the mechanisms by which dietary cholesterol might contribute to hepatic fibrogenesis.
C57BL/6 mice were fed a high-cholesterol diet or a control diet for 4 weeks; liver fibrosis then was induced by bile-duct ligation or carbon tetrachloride administration. Hepatic stellate cells (HSCs) were isolated from mice fed high-cholesterol diets or from Niemann-Pick type C1-deficient mice, which accumulate intracellular free cholesterol.
After bile-duct ligation or carbon tetrachloride administration, mice fed high-cholesterol diets had significant increases in liver fibrosis and activation of HSCs compared with mice fed control diets. There were no significant differences in the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation, between mice fed high-cholesterol or control diets. Levels of free cholesterol were much higher in HSCs from mice fed high-cholesterol diets than those fed control diets. In cultured HSCs, accumulation of free cholesterol in HSCs increased levels of Toll-like receptor 4 (TLR4), leading to down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor (a pseudoreceptor for transforming growth factor [TGF]β); the HSCs became sensitized to TGFβ-induced activation. Liver fibrosis was not aggravated by the high-cholesterol diet in C3H/HeJ mice, which express a mutant form of TLR4; HSCs that express mutant TLR4 were not activated by accumulation of free cholesterol.
Dietary cholesterol aggravates liver fibrosis because free cholesterol accumulates in HSCs, leading to increased TLR4 signaling, down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor, and sensitization of HSC to TGFβ. This pathway might be targeted by antifibrotic therapies.
一些研究表明，膳食胆固醇在肝纤维化的进展中起作用。我们研究了膳食胆固醇促进肝纤维化形成的机制。
C57BL/6 小鼠喂食高胆固醇饮食或对照饮食 4 周；然后通过胆管结扎或四氯化碳给药诱导肝纤维化。从喂食高胆固醇饮食的小鼠或尼曼-匹克 C1 缺陷型（Niemann-Pick type C1-deficient mice）小鼠（其细胞内游离胆固醇蓄积）分离肝星状细胞（hepatic stellate cells，HSCs）。
胆管结扎或四氯化碳给药后，与喂食对照饮食的小鼠相比，喂食高胆固醇饮食的小鼠肝纤维化和 HSCs 激活显著增加。在肝细胞损伤或肝炎症程度方面，包括肝细胞凋亡或枯否细胞激活，喂食高胆固醇或对照饮食的小鼠之间没有显著差异。与喂食对照饮食的小鼠相比，喂食高胆固醇饮食的小鼠的 HSCs 中游离胆固醇水平高得多。在培养的 HSCs 中，HSCs 中游离胆固醇的蓄积增加了 Toll 样受体 4（Toll-like receptor 4，TLR4）的水平，导致骨形态发生蛋白和激活素膜结合抑制剂（转化生长因子[TGF]β的伪受体）的下调；HSCs 对 TGFβ诱导的激活变得敏感。在表达突变型 TLR4 的 C3H/HeJ 小鼠中，高胆固醇饮食不会加重肝纤维化；表达突变型 TLR4 的 HSCs 不会因游离胆固醇蓄积而被激活。
膳食胆固醇加重肝纤维化，因为游离胆固醇在 HSCs 中蓄积，导致 TLR4 信号转导增加、骨形态发生蛋白和激活素膜结合抑制剂下调以及 HSC 对 TGFβ的敏感性增加。该途径可能成为抗纤维化治疗的靶点。
