Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation-related protein (ADRP).
Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation-related protein (ADRP).
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DOI：
10.1002/jcp.22063
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发表时间：
2010-06
影响因子：
5.6
通讯作者：
Friedman, Scott L.
中科院分区：
文献类型：
--
作者：
Lee, Ting Fang;Mak, Ki M.;Rackovsky, Ori;Lin, Yun-Lian;Kwong, Allison J.;Loke, Johnny C.;Friedman, Scott L.
肝星状细胞（HSC）在细胞质脂滴中储存类维生素A和甘油三酯。肝纤维化中HSC活化的两个显著特征是脂滴沿着减少，同时α-平滑肌肌动蛋白（α-SMA）增加，但这些反应与HSC活化之间的联系仍不清楚。在非脂肪细胞中，脂肪分化相关蛋白（ADRP）包覆脂滴并调节其形成和脂解;然而，其在HSC中的功能尚不清楚。在此，我们观察到，在人肝切片或原代HSC培养物中，ADRP定位于HSC的脂滴，并且与肝纤维化和培养物活化的HSC中的脂滴损失一致的染色减少，与HSC活化一致。在LX-2人永生化HSC中，脂滴较少，具有活化HSC的特征，我们发现棕榈酸酯上调ADRP mRNA被视黄醇增强，伴随着ADRP蛋白的增加，棕榈酸视黄酯的产生和脂滴的形成。ADRP诱导也导致α-SMA mRNA及其蛋白表达降低，而ADRP敲除小干扰RNA（siRNA）使α-SMA表达正常化。此外，ADRP诱导的视黄醇和棕榈酸酯导致胶原蛋白I和基质金属蛋白酶-2 mRNA的表达减少，与活化的HSC相关的纤维化基因，而增加基质金属蛋白酶-1 mRNA; ADRP敲低与siRNA逆转这些变化。金属蛋白酶组织抑制剂-1不受影响。因此，由视黄醇和棕榈酸酯介导的ADRP上调促进HSC活化的下调，并且在功能上与纤维化基因的表达相关。
Hepatic stellate cells (HSCs) store retinoids and triacylglycerols in cytoplasmic lipid droplets. Two prominent features of HSC activation in liver fibrosis are loss of lipid droplets along with increase of α-smooth muscle actin (α-SMA), but the link between these responses and HSC activation remains elusive. In non-adipose cells, adipose differentiation-related protein (ADRP) coats lipid droplets and regulates their formation and lipolysis; however its function in HSCs is unknown. Here, we observed, in human liver sections or primary HSC culture, ADRP localization to lipid droplets of HSCs, and reduced staining coincident with loss of lipid droplets in liver fibrosis and in culture-activated HSCs, consistent with HSC activation. In the LX-2 human immortalized HSCs, with scant lipid droplets and features of activated HSCs, we found that the upregulation of ADRP mRNA by palmitate is potentiated by retinol, accompanied by increased ADRP protein, generation of retinyl palmitate and lipid droplet formation. ADRP induction also led to decreased expression of α-SMA mRNA and its protein, while ADRP knockdown with small interfering RNA (siRNA) normalized α-SMA expression. Furthermore, ADRP induction by retinol and palmitate resulted in decreased expression of collagen I and matrix metalloproteinase-2 mRNA, fibrogenic genes associated with activated HSCs, while increasing matrix metalloproteinase-1 mRNA; ADRP knockdown with siRNA reversed these changes. Tissue inhibitor of metalloproteinase-1 was not affected. Thus, ADRP upregulation mediated by retinol and palmitate promotes downregulation of HSC activation and is functionally linked to the expression of fibrogenic genes.
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影响因子：
7.7
作者：
Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
通讯作者：
Sztalryd, Carole
影响因子：
4.8
作者：
Cao, Q;Mak, KM;Lieber, CS
通讯作者：
Lieber, CS
影响因子：
6
作者：
Ding, XK;Saxena, NK;Anania, FA
通讯作者：
Anania, FA
影响因子：
5.3
作者：
Chang, BHJ;Li, L;Chan, L
通讯作者：
Chan, L
影响因子：
13.5
作者：
FRIEDMAN, SL;ROCKEY, DC;YAMASAKI, G
通讯作者：
YAMASAKI, G