Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

• Published in: Hepatology international Vol. 15; no. 5; pp. 1122 - 1135
• Main Authors: Yang, Aiting, Yan, Xuzhen, Fan, Xu, Shi, Yiwen, Huang, Tao, Li, Weiyu, Chen, Wei, Jia, Jidong, You, Hong
• Format: Journal Article
• Language: English
• Published: New Delhi Springer India 01.10.2021; Springer Nature B.V
• Subjects: Abnormalities; Adipose tissue; Amino Acid Oxidoreductases - genetics; Amino acids; Animal models; Animals; Biopsy; Choline; Colorectal Surgery; Crosslinking; Diet; Disease Models, Animal; Extracellular matrix; Fatty liver; Fibrosis; Gene expression; Hepatic Stellate Cells - pathology; Hepatology; Humans; Inflammation; Inflammation - pathology; Leptin; Lipids; Lipogenesis; Liver; Liver - pathology; Liver Cirrhosis - pathology; Liver diseases; Lysyl oxidase; Medicine; Medicine & Public Health; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Nutrient deficiency; Obesity; Original Article; Pathogenesis; Steatosis; Stellate cells; Surgery; NAFLD; Leptin; Liver fibrosis; Hepatic stellate cell; Lipid metabolism; Crosslink; ECM; LOXL1; Non-obese NASH; CDAA
• ISSN: 1936-0533; 1936-0541; 1936-0541
• DOI: 10.1007/s12072-021-10210-w

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/fl Gfap cre ; Loxl1 fl/fl as littermate controls) and then examined liver pathology and metabolic profiles in Loxl1 fl/fl Gfap 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.