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 brosis 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 / mice to selectively delete Loxl1 in hepatic stellate cells (HSCs) (Loxl1 / Gfap cre ; Loxl1 / as littermate controls) and then examined liver pathology and metabolic context in Loxl1 / Gfap cre fed a choline-de cient L-amino acid-de ned (CDAA) diet or an isocaloric control diet for 16 weeks. We con rmed study ndings in 23 patients with biopsy-proven NAFLD. Results: LOXL1 was signi cantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-speci c deletion of Loxl1 model, we found that Loxl1 de cient in HSCs ameliorated CDAA-induced in ammation and brosis, with reduced expression of pro-in ammation and pro-brogenic genes. Interestingly, CDAA-fed Loxl1 de cient 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 brosis 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 brosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.