Background and aims

Lysyl oxidase-like-1 (LOXL1), a vital cross-linking enzyme in extracellular matrix (ECM) maintenance, promotes fibrosis via enhancement of ECM stability. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied.

Methods

We generated Loxl1^fl/fl mice to selectively delete LOXL1 in hepatic stellate cells (HSCs) (Loxl1^fl/flGfap^cre; Loxl1^fl/fl as littermate controls) and then examined liver pathology and metabolic profiles in Loxl1^fl/flGfap^cre fed with either a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. Thereafter, the findings from the animal model were confirmed in 23 patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD).

Results

LOXL1 was significantly increased in CDAA induced non-obese NASH compared with the control diet, and LOXL1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes in the HSCs-specific LOXL1 knockout mice model. Interestingly, LOXL1 deficient in HSCs could attenuate hepatic steatosis and reverse the metabolic disorder by restoring adipose tissue function without altering the effect of hepatic lipogenesis gene expression in non-obese NASH model. More importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas it was inversely correlated with leptin levels, especially in non-obese NAFLD patients.

Conclusion

LOXL1 may contribute to fibrosis progression in non-obese NAFLD, and HSCs-specific knockout of LOXL1 attenuated liver steatosis, inflammation, fibrosis, , and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

中文翻译：

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肝星状细胞特异性 LOXL1 缺乏可消除非肥胖 NASH 小鼠的肝脏炎症、纤维化并纠正脂质代谢异常

背景和目标

Lysyl oxidase-like-1 (LOXL1) 是细胞外基质 (ECM) 维持中的一种重要交联酶，通过增强 ECM 稳定性来促进纤维化。然而，LOXL1 在非酒精性脂肪性肝炎 (NASH) 发病机制中的潜在作用之前尚未研究过。

方法

我们生成 Loxl1 ^fl/fl小鼠以选择性删除肝星状细胞 (HSC) 中的 LOXL1（Loxl1 ^fl/fl Gfap ^cre；Loxl1 ^fl/fl作为同窝对照），然后检查 Loxl1 fl/fl Gfap cre 中的肝脏病理学^和代谢^谱与缺乏胆碱的 L-氨基酸确定 (CDAA) 饮食或等热量对照饮食一起 16 周。此后，来自动物模型的研究结果在 23 名经活检证实的非酒精性脂肪肝病 (NAFLD) 患者中得到证实。

结果

与对照饮食相比，CDAA 诱导的非肥胖 NASH 中 LOXL1 显着增加，HSCs 中缺乏的 LOXL1 改善了 CDAA 诱导的炎症和纤维化，在 HSCs 特异性 LOXL1 敲除小鼠中促炎和促纤维化基因的表达降低模型。有趣的是，在非肥胖 NASH 模型中，缺乏 HSC 的 LOXL1 可以通过恢复脂肪组织功能来减轻肝脂肪变性并逆转代谢紊乱，而不改变肝脂肪生成基因表达的影响。更重要的是，对 NAFLD 患者血清 LOXL1 和瘦素水平的分析表明，LOXL1 与组织学纤维化进展呈正相关，而与瘦素水平呈负相关，尤其是在非肥胖 NAFLD 患者中。

结论

LOXL1 可能有助于非肥胖 NAFLD 的纤维化进展，而 HSCs 特异性敲除 LOXL1 可减轻肝脏脂肪变性、炎症、纤维化，并改善脂质代谢异常。因此，LOXL1 抑制可能作为 NASH 的新治疗策略。