Institute of Biomedical Research, Liaocheng University, Liaocheng, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Hepatology-Gastroenterology, Second Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Biochim Biophys Acta Gene Regul Mech. 2019 Jun;1862(6):609-618. doi: 10.1016/j.bbagrm.2019.03.001. Epub 2019 Apr 2.
Although hepatic stellate cells (HSC) represent the major source of fibrogenesis in the liver under various pathological conditions, other cell types including hepatic parenchymal cells (hepatocytes) also contribute to HSC activation and hence liver fibrosis. The underlying mechanism, however, is poorly defined. Here we report that hepatocytes exposed to high concentrations of glucose (HG) emit a pro-fibrogenic cue as evidenced by the observation that primary HSCs cultured in conditioned media (CM) collected from hepatocytes exposed to HG up-regulated the production of extracellular matrix (ECM) proteins compared to CM collected from hepatocytes exposed to low glucose. We further identified the pro-fibrogenic cue from hepatocytes to be connective tissue growth factor (CTGF) because either depletion of endogenous CTGF in hepatocytes with siRNA or the addition of a CTGF-specific neutralizing antibody to the CM blunted the pro-fibrogenic effect elicit by HG treatment. Of interest, we discovered that genetic ablation or pharmaceutical inhibition of the transcriptional modulator MKL1 in hepatocytes also abrogated the HG-induced pro-fibrogenic effects. Mechanistically, MKL1 interacted with AP-1 and SMAD3 to trans-activate CTGF in hepatocytes in response to HG treatment. In conclusion, our data suggest that MKL1 contribute to HSC activation in a non-autonomous fashion by promoting CTGF transcription in hepatocytes.
虽然肝星状细胞 (HSC) 在各种病理条件下代表肝脏纤维化的主要来源，但其他细胞类型，包括肝实质细胞 (肝细胞)，也有助于 HSC 的激活，从而导致肝纤维化。然而，其潜在机制尚未明确。在这里，我们报告说，暴露于高浓度葡萄糖 (HG) 的肝细胞会发出促纤维化信号，这一观察结果表明，与暴露于低葡萄糖的肝细胞收集的条件培养基 (CM) 相比，培养在来自暴露于 HG 的肝细胞的 CM 中的原代 HSC 上调了细胞外基质 (ECM) 蛋白的产生。我们进一步确定肝细胞中的促纤维化信号是结缔组织生长因子 (CTGF)，因为用 siRNA 耗尽肝细胞中的内源性 CTGF 或向 CM 中添加 CTGF 特异性中和抗体，均可削弱 HG 处理引起的促纤维化作用。有趣的是，我们发现，肝细胞中转录调节剂 MKL1 的基因缺失或药物抑制也消除了 HG 诱导的促纤维化作用。在机制上，MKL1 与 AP-1 和 SMAD3 相互作用，以响应 HG 处理在肝细胞中转录激活 CTGF。总之，我们的数据表明，MKL1 通过促进肝细胞中 CTGF 的转录，以非自主的方式促进 HSC 的激活。
