Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal-/- Mice
Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal-/- Mice
复制标题
DOI：
10.1016/j.ajpath.2015.05.021
复制
发表时间：
2015-09-01
影响因子：
6
通讯作者：
Yan, Cong
中科院分区：
文献类型：
--
作者：
Du, Hong;Zhao, Ting;Yan, Cong
肝脏是脂肪合成和代谢的主要器官。在小鼠(Lal(-/-))中，由于中性脂肪储存在肝细胞和Kupffer细胞中，导致小鼠溶酶体酸性脂肪酶(Lal；正式名称LIPA，由LIPA编码)缺陷导致肝脏增大。为探讨LAL在肝细胞中的功能作用，将肝激活启动子(LAP)驱动的TTA转基因与Lal(-/-)基因敲除(LAP-TG/K0)(LAP-TG/K0)三重小鼠杂交，建立了肝细胞特异性表达人LAL(-/-)的方法。LAP-TG/K0三系小鼠肝细胞特异性表达hlal可使小鼠肝脏缩小至正常大小。通过减少肝细胞和Kupffer细胞中的脂肪储存来达到这一水平。在LAL(-/-)小鼠的肝脏中，HLAL的表达减少了促肿瘤髓系来源的抑制细胞。结果，B16黑色素瘤向肝脏的转移几乎完全被阻断。肝脏中多种促肿瘤细胞因子或趋化因子的表达和分泌也显著减少。由于Hal是一种分泌性蛋白质，其他部分(如血液、脾和肺)的Lal(-/-)表型也得到了改善，包括系统性地减少了髓系来源的抑制细胞，增加了CD4(+)和CD8(+)T和B淋巴细胞，并减少了B16黑色素瘤在肺部的转移。这些结果支持肝细胞中LAL是控制中性脂代谢、肝脏动态平衡、免疫反应和肿瘤转移的关键代谢酶的概念。
The liver is a major organ for lipid synthesis and metabolism. Deficiency of lysosomal acid lipase (LAL; official name Lipa, encoded by Lipa) in mice (lal(-/-)) results in enlarged Liver size due to neutral Lipid storage in hepatocytes and Kupffer cells. To test the functional role of LAL in hepatocyte, hepatocytespecific expression of human LAL (hLAL) in lal(-/-) mice was established by cross-breeding of liveractivated promoter (LAP)-driven tTA transgene and (tet0)(7)-CMV-hLAL transgene with lal(-/-) knockout (KO) (LAP-Tg/K0) triple mice. Hepatocyte-specific expression of hLAL in LAP-Tg/K0 triple mice reduced the liver size to the normal. Level by decreasing lipid storage in both hepatocytes and Kupffer cells. hLAL expression reduced tumor-promoting myeloid-derived suppressive cells in the liver of lal(-/-) mice. As a result, B16 melanoma metastasis to the Liver was almost completely blocked. Expression and secretion of multiple tumor-promoting cytokines or chemokines in the liver were also significantly reduced. Because hLAL is a secretory protein, lal(-/-) phenotypes in other compartments (eg, blood, spleen, and lung) also ameliorated, including systemic reduction of myeloid-derived suppressive cells, an increase in CD4(+) and CD8(+) T and B lymphocytes, and reduced B16 melanoma metastasis in the lung. These results support a concept that LAL in hepatocytes is a critical metabolic enzyme in controlling neutral lipid metabolism, liver homeostasis, immune response, and tumor metastasis.