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High Fat Feeding Primes Mice to Binge Alcohol‐induced Liver Injury: Critical Role of Cathelicidin as a Chemoattractant
Author(s) -
Li Fengyuan,
Liu Yunhuan,
Gu Zelin,
Jiang Mengwei,
Zhang Lihua,
McClain Craig J.,
Feng Wenke
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06216
Subject(s) - liver injury , cathelicidin , medicine , endocrinology , steatosis , alcohol , inflammation , alcoholic liver disease , chemokine , infiltration (hvac) , chemistry , innate immune system , biochemistry , cirrhosis , receptor , physics , thermodynamics
Background Alcohol consumption and obesity are known synergistic risk factors of steatohepatitis. Combination of high fat diet (HFD) and acute alcohol synergistically induced acute liver inflammation via enhanced hepatic neutrophil infiltration. CRAMP (Cathelicidin‐related antimicrobial peptide), the murine ortholog of LL‐37, which is the only known member of human cathelicidin antimicrobial peptide family, possess both anti‐ and pro‐inflammatory activity. Our previous studies showed that CRMAP deficiency exacerbated binge‐on‐chronic alcohol‐induced liver injury. Here we aimed to investigate the role of CRAMP in alcohol‐induced liver injury in HFD fed mice, and to explore the underlying mechanism. Methods CRAMP KO mice ( Camp −/− ) and wild type (WT) mice were fed control diet (CD) or HFD for 10 weeks, a bolus of alcohol was gavaged 9 hours before sample harvesting. Results Ten‐week HFD + acute alcohol markedly induced liver steatosis and injury in WT mice, reflected by significantly increased liver macrosteatosis and serum levels of AST and ALT. Immunofluorescent assay showed a significantly stronger staining of Ly6G in the livers of mice treated with HFD + acute alcohol compared to CD feeding + acute alcohol, indicating an increased neutrophil infiltration. Interestingly, HFD+acute alcohol treatment significantly increased hepatic protein levels of CRAMP, which co‐localized with Ly6G‐positive neutrophils. In addition, hepatic mRNA expression of chemokines, Mcp‐1 and Cxcl‐2 , was markedly increased. Depletion of Camp gene ( Camp −/− ) markedly reduced HFD + acute alcohol‐induced liver steatosis, injury and neutrophil infiltration, along with reduced expression of Mcp‐1 . Importantly, feeding Camp −/− mice with HFD + acute alcohol significantly reduced the mRNA expression level of Cxcr ‐2, a known CRAMP receptor. In vitro study showed that synthetic CRAMP peptide increased neutrophil migration, which was dependent on Cxcr‐2 expression upon treatment by fatty acid and ethanol. In addition, significantly decreased mRNA levels of hepatic Tgf‐β and Col‐1a1 were found in Camp −/− mice compared to WT mice, suggesting that CRAMP may play a role in hepatic stellate cells activation. Conclusions HFD + acute alcohol treatment synergistically induces liver injury through systemic upregulation of chemoattractant CRAMP and subsequent enhancement of hepatic neutrophil infiltration. CRAMP deficiency protects against acute alcohol‐induced steatohepatitis in the HFD primed mice. Support or Funding Information Supported by grants from NIHSchematic hypothesis of CRAMP‐mediated neutrophils infiltration in HFD and alcohol‐induced liver injury in mice