Department of Anatomy and Convergence Medical Science , College of Medicine , Institute of Health Sciences , Gyeongsang National University , Jinju , Republic of Korea.
College of Pharmacy , Research Institute of Pharmaceutical Sciences , Gyeongsang National University , Jinju , Republic of Korea.
Hepatology. 2023 Mar 1;77(3):888-901. doi: 10.1002/hep.32569. Epub 2023 Feb 17.
In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.
Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs.
LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.
在肥胖症和 2 型糖尿病患者中，瘦素通过激活肝星状细胞（HSCs）促进胰岛素抵抗，并导致 NASH 的进展。然而，瘦素缺乏性肥胖症中触发 HSC 激活的致病机制仍不清楚。本研究旨在确定 HSC 靶向的脂联素-2（LCN2）如何介导单纯性脂肪变性向 NASH 的转变。
雄性野生型（WT）和 ob/ob 小鼠喂食高脂肪饮食（HFD）20 周，建立具有纤维化的 NASH 动物模型。ob/ob 小鼠接受热量限制或重组瘦素治疗。也将缺乏瘦素和 lcn2 的双敲除（DKO）小鼠喂食 HFD 20 周。此外，喂食 HFD 的 ob/ob 小鼠用三氯化钆处理以耗尽枯否细胞。LX-2 人 HSCs 和 ob/ob 小鼠的原代 HSCs 用于研究 LCN2 对 HSC 激活的影响。与正常饮食喂养的 ob/ob 小鼠或 HFD 喂养的 WT 小鼠相比，HFD 喂养的 ob/ob 小鼠的血清和肝 LCN2 表达水平显著升高，这些变化与肝纤维化和增加的肝α-SMA/基质金属蛋白酶 9（MMP9）/信号转导和转录激活因子 3（STAT3）蛋白水平密切相关。与 HFD 喂养的 ob/ob 小鼠相比，HFD 喂养的 DKO 小鼠的α-SMA 蛋白明显减少。特别是，在 HFD 喂养的 ob/ob 小鼠的 HSCs 中，LCN2 和α-SMA 的共定位增加。在 ob/ob 小鼠的原代 HSCs 中，外源性 LCN2 处理诱导 HSC 激活和 MMP9 分泌。相比之下，LCN2 受体 24p3R 缺失或 STAT3 抑制剂减少了原代 HSCs 的激活和迁移。
LCN2 通过α-SMA/MMP9/STAT3 信号作为瘦素缺乏性肥胖症中 HSC 激活的关键介质，从而加重 NASH。
