Hepatic Stellate Cells-Specific Loxl1 Deficiency Abrogates Hepatic Inflammation, Fibrosis, and Corrects Lipid Metabolic Abnormalities in Non-Obese NASH Mice

Abstract

Background & Aims: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in fibrosis via mediating ECM stabilization. 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) (Loxl1fl/flGfapcre; Loxl1fl/fl as littermate controls) and then examined liver pathology and metabolic context in Loxl1fl/flGfapcre fed a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. We confirmed study findings in 23 patients with biopsy-proven NAFLD. Results: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-specific deletion of Loxl1 model, we found that Loxl1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes. Interestingly, CDAA-fed Loxl1 deficient mice was associated with improved body weight and attenuated hepatic steatosis and to an up-regulation of leptin in adipose tissue and in serum, without changes in hepatic lipogenesis gene expression, compared with CDAA-fed control mice. Most importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas was inversely correlated with leptin levels, especially in non-obese NAFLD patients. Conclusion: In a mouse model of CDAA-induced non-obese NASH, selective deletion of Loxl1 from HSCs attenuated steatohepatitis, hepatic fibrosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH. Funding Statement: This study was supported by the National Natural Science Foundation of China (81670539 and 81500456). Declaration of Interests: The authors disclose no conflicts. Ethics Approval Statement: (Human) The Ethics Committee of Beijing Friendship Hospital approved study (No.: 2018-P2-228-02). (Animal) This study was approved by the Institutional Animal Care and Usage Committee of the Beijing Friendship Hospital, Capital Medical University, Beijing, China.