Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability
Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability
复制标题
甾醇调节元件结合蛋白 (SREBP)-1c-Null 小鼠部分肝切除后肝脏再生增强与肝细胞胆固醇可用性增加相关
DOI：
10.1159/000490030
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Su, Wen
中科院分区：
文献类型：
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作者：
Peng, Jun;Yu, Jingwei;Su, Wen
背景/目标：在高峰增殖过程之前肝细胞内的瞬时脂质积聚是肝再生的特征性特征。然而，负责这种脂质积聚的分子介质及其功能尚未明确。固醇调节元件结合蛋白-1c（SREBP-1c）是调节肝脏脂质稳态的关键转录因子。我们推测SREBP-1c缺陷诱导的脂质代谢改变可能影响肝细胞增殖和肝再生。方法：采用野生型C57 BL/6 J（WT）和Srebp-1c-/-小鼠，行2/3肝部分切除术（PH）。酶比色法测定血清和肝脏脂质含量。油红O染色及免疫组化染色检测肝脂滴。通过实时PCR和/或免疫印迹法测定参与脂质代谢和细胞增殖的基因的肝脏表达。分别通过BrdU染色和Srebp-1c-/-小鼠的再生肝叶重量来评估肝细胞增殖和肝再生。结果如下：Srebp-1c-/-小鼠显示减少甘油三酯和脂肪酸，但增加胆固醇在肝脏PH前。在响应PH，肝细胞DNA合成升高，细胞周期进程延长Srebp-1c-/-小鼠，这是与增强肝再生。然而，Srebp-1c-/-小鼠在肝再生过程中与WT小鼠相比具有相当的甘油三酯和脂肪酸含量以及相关基因的表达。相反，SREBP-1c缺陷诱导的胆固醇代谢改变在PH后的肝再生期间被保留。Srebp-1c-/-小鼠在PH后比WT小鼠表现出更高的胆固醇含量和肝中SREBP-2和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的增强表达。在Srebp-1c-/-小鼠PH后观察到参与胆固醇消除的基因下调。结论：SREBP-1c缺乏症在小鼠中没有干扰甘油三酯和脂肪酸代谢，但与肝再生过程中胆固醇谱的显着变化后PH。这些结果表明，增加肝细胞胆固醇储存和胆固醇的可用性与增强肝再生确定在Srebp-1c-/-小鼠。这项研究还表明，为增殖的肝细胞提供必要的胆固醇水平并保持适当的胆固醇代谢是正常肝再生所必需的。
Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.