Department of Pathology, Fudan University Zhongshan Hospital, Shanghai, China.
Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.
Am J Physiol Gastrointest Liver Physiol. 2020 Jul 1;319(1):G87-G96. doi: 10.1152/ajpgi.00380.2019. Epub 2020 Jun 1.
Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) plays a critical role in hepatic energy homeostasis. Liver X receptors (LXRs) are implicated in multiple physiological functions, including the inhibition of hepatocyte proliferation and regulation of fatty acid and cholesterol metabolism. We have previously reported that SULT2B1b promotes hepatocyte proliferation by inactivating LXR signaling in vivo and in vitro, leading to our hypothesis that SULT2B1b promotes fatty liver regeneration. In the present study, female C57BL/6 and S129 mice were fed a high-fat diet for 8 wk to establish a nonalcoholic fatty liver disease (NAFLD) mouse model. 70% partial hepatectomy (PH) was performed to induce liver regeneration. Our experiments revealed that the SULT2B1b overexpression significantly promotes the regeneration of hepatocytes in NAFLD C57BL/6 mice after PH, increasing liver regrowth by 11% within 1 day, and then by 21%, 33%, and 24% by 2, 3, and 5 days post-PH, respectively. Compared with the wild-type NAFLD S129 mice, SULT2B1 deletion NAFLD S129 mice presented reduced hepatocyte regeneration at postoperative , as verified by decreased liver regrowth (37.4% vs. 46.1%, < 0.05) and the results of immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. Moreover, LXRα signaling and SULT2B1b expression are highly correlated in the regeneration of NAFLD mouse liver; SULT2B1b overexpression suppresses LXRα signaling, while the LXRα-signaling agonist T0901317 blocks SULT2B1b-induced hepatocyte regeneration in NAFLD mouse liver. Thus, the upregulation of SULT2B1b may promote hepatocyte regeneration via the suppression of LXRα activation in NAFLD mice, providing a potential strategy for improving hepatic-steatosis-related liver regeneration disorders. This study demonstrates for the first time that hydroxysteroid sulfotransferase 2B1b (SULT2B1b) overexpression promotes the regeneration of fatty liver after partial hepatectomy in mice with nonalcoholic fatty liver disease, while reducing triglyceride accumulation in the regenerative fatty liver. Liver X receptor signaling may be crucial in the SULT2B1b-mediated regeneration of fatty liver. Thus, SULT2B1b may be a potential target for treating hepatic steatosis-related liver regeneration disorders.
羟甾类激素硫酸转移酶 2B1b（SULT2B1b）在肝脏能量稳态中发挥关键作用。肝 X 受体（LXRs）参与多种生理功能，包括抑制肝细胞增殖和调节脂肪酸和胆固醇代谢。我们之前的研究表明，SULT2B1b 通过体内和体外失活 LXR 信号促进肝细胞增殖，这导致我们假设 SULT2B1b 促进脂肪性肝再生。在本研究中，雌性 C57BL/6 和 S129 小鼠接受高脂肪饮食 8 周以建立非酒精性脂肪性肝病（NAFLD）小鼠模型。进行 70%部分肝切除术（PH）以诱导肝再生。我们的实验表明，SULT2B1b 过表达在 PH 后显著促进 NAFLD C57BL/6 小鼠的肝细胞再生，在 1 天内使肝再生增加 11%，然后在术后第 2、3 和 5 天分别增加 21%、33%和 24%。与野生型 NAFLD S129 小鼠相比，SULT2B1 缺失的 NAFLD S129 小鼠在术后呈现出较低的肝细胞再生，这通过肝再生减少（37.4%对 46.1%， < 0.05）和免疫组织化学染色、定量实时聚合酶链反应和 Western blot 分析结果得到证实。此外，在 NAFLD 小鼠肝再生过程中，LXRα信号和 SULT2B1b 表达高度相关；SULT2B1b 过表达抑制 LXRα信号，而 LXRα 信号激动剂 T0901317 阻断了 NAFLD 小鼠肝中 SULT2B1b 诱导的肝细胞再生。因此，在 NAFLD 小鼠中，SULT2B1b 的上调可能通过抑制 LXRα 激活来促进肝细胞再生，为改善与肝脂肪变性相关的肝再生障碍提供了一种潜在策略。本研究首次证明，羟甾类激素硫酸转移酶 2B1b（SULT2B1b）过表达可促进非酒精性脂肪性肝病小鼠部分肝切除后的脂肪肝再生，同时减少再生脂肪性肝中的甘油三酯积累。肝 X 受体信号可能在 SULT2B1b 介导的脂肪肝再生中至关重要。因此，SULT2B1b 可能是治疗与肝脂肪变性相关的肝再生障碍的潜在靶点。
