Department of Molecular Genetics, Electron Microscopy Unit of Molecular Cell Biology, and Pathology, Nutrition and Toxicology Research (NUTRIM) Institute of Maastricht, University of Maastricht, Maastricht, The Netherlands.
PLoS One. 2012;7(3):e34378. doi: 10.1371/journal.pone.0034378. Epub 2012 Mar 28.
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).
METHODS & RESULTS: Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.
CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH.
非酒精性脂肪性肝炎（NASH）的特征为脂肪变性和炎症，可进一步进展为纤维化和肝硬化。最近，我们证实了主要清道夫受体 CD36 和巨噬细胞清道夫受体 1（MSR1）的双重缺失，这对于摄取修饰的富含胆固醇的脂蛋白至关重要，可减少 NASH。这些受体对 NASH 的个体贡献以及它们促进炎症的细胞内机制尚未确定。我们假设 CD36 和 MSR1 通过影响枯否细胞（KCs）内的细胞内胆固醇分布，独立地促成 NASH 中的炎症发作。
将载脂蛋白 E 基因敲除（Ldlr(-/-)）小鼠的骨髓移植为野生型（Wt）、CD36(-/-)或 MSR1(-/-)，并给予西方饮食 3 个月。与 Wt-tp 小鼠相比，CD36(-/-)-和 MSR1(-/-)-移植（tp）小鼠的肝炎症明显减轻。尽管所有组的 KC 内总胆固醇含量相似，但 CD36(-/-)-和 MSR1(-/-)-tp 小鼠的 KC 内细胞质胆固醇积累增加，而 Wt-tp 小鼠的溶酶体胆固醇积累增加。
CD36 和 MSR1 以相似且独立的方式促进 NASH 中炎症的进展。这些受体表达相关炎症反应的一个可能解释可能是 KCs 内胆固醇转运异常。这些数据为 NASH 的预防和治疗提供了新的依据。
