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

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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.

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Funding

This study was supported by the National Natural Science Foundation of China (81970524 and 81500456).

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Authors and Affiliations

  1. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China

    Aiting Yang, Tao Huang & Wei Chen

  2. Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of China

    Xuzhen Yan, Xu Fan, Yiwen Shi, Weiyu Li, Jidong Jia & Hong You

  3. Beijing Clinical Medicine Institute, Beijing, 100050, People’s Republic of China

    Aiting Yang, Tao Huang, Wei Chen, Jidong Jia & Hong You

  4. National Clinical Research Center of Digestive Diseases, Beijing, 100050, People’s Republic of China

    Aiting Yang, Xuzhen Yan, Xu Fan, Yiwen Shi, Tao Huang, Weiyu Li, Wei Chen, Jidong Jia & Hong You

Authors
  1. Aiting Yang
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  2. Xuzhen Yan
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  3. Xu Fan
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  4. Yiwen Shi
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  5. Tao Huang
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  7. Wei Chen
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  8. Jidong Jia
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  9. Hong You
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Contributions

AY, and HY conceived the study. AY, XY, XF, YS, TH, WL, WC, JJ, and HY performed experiments or analyzed the data. AY drafted the manuscript, and all authors read or revised the manuscript.

Corresponding author

Correspondence to Hong You.

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Conflict of interest

The authors Aiting Yang, Xuzhen Yan, Xu Fan, Yiwen Shi, Tao Huang, Weiyu Li, Wei Chen, Jidong Jia and Hong You declared that they have no conflict of interest.

Animal research

This study was approved by the Institutional Animal Care and Usage Committee of the Beijing Friendship Hospital, Capital Medical University (No.:20-2002).

Consent to participate

The study was conducted in accordance with the principles enshrined in the Declaration of Helsinki and the Good Clinical Practices. The Ethics Committee of Beijing Friendship Hospital, Capital Medical University approved study (No.: 2018-P2-228-02).

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All authors had access to the study data and reviewed and approved the final manuscript.

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Yang, A., Yan, X., Fan, X. et al. Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice. Hepatol Int 15, 1122–1135 (2021). https://doi.org/10.1007/s12072-021-10210-w

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  • DOI: https://doi.org/10.1007/s12072-021-10210-w

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