Abstract
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. We generated Loxl1fl/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 profiles in Loxl1fl/flGfapcre 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). 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. 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease around the worldwide
Based on our previously findings supporting Lysyl oxidase-like-1 (LOXL1) expression in hepatic stellate cells (HSCs) was strongly associated with liver fibrosis progression[9]
We found that LOXL1 expression in activated HSCs was significantly diminished in Loxl1fl/flGfapcre mice; interestingly, we found that LOXL1 positioned between the plates of hepatocytes (Fig. 1E)
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease around the worldwide. NAFLD display a wide spectrum of pathologies ranging from steatosis, steatohepatitis (nonalcoholic steatohepatitis, NASH) and fibrosis to cirrhosis and/or hepatocellular carcinoma (HCC) [2]. Significant steps in the progression from NASH to cirrhosis and liver failure involve extracellular matrix (ECM) remodeling and fibrosis, which is characterized by the abundant production of ECM proteins (consisting of collagens, elastin and other proteins) and incomplete fibrinolysis [5]. Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in fibrosis via mediating ECM stabilization. The potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied
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