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

Hepatol Int. 2021 Oct;15(5):1122-1135. doi: 10.1007/s12072-021-10210-w. Epub 2021 May 20.

Abstract

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 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).

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.

Keywords: CDAA; Crosslink; ECM; Hepatic stellate cell; LOXL1; Leptin; Lipid metabolism; Liver fibrosis; NAFLD; Non-obese NASH.

MeSH terms

  • Amino Acid Oxidoreductases / genetics
  • Animals
  • Disease Models, Animal
  • Hepatic Stellate Cells / pathology
  • Humans
  • Inflammation / pathology
  • Lipids
  • Liver / pathology
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / pathology

Substances

  • Lipids
  • Amino Acid Oxidoreductases
  • LOXL1 protein, human