Histidine‐Rich Glycoprotein Alleviates Liver Ischemia/Reperfusion Injury in Mice With Nonalcoholic Steatohepatitis

Abstract

Hepatic ischemia/reperfusion injury (IRI) is a major complication of liver surgery and transplantation, especially in patients with nonalcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to IRI has not been fully clarified. We investigated the role of liver‐produced histidine‐rich glycoprotein (HRG) in NASH IRI. A NASH mouse model was established using C57BL/6J mice fed a methionine‐choline–deficient diet (MCDD) for 6 weeks. The MCDD and standard diet groups were exposed to 60 minutes of partial hepatic ischemia/reperfusion (I/R). We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. IRI increased HRG expression in the standard diet group, but not in the MCDD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and the formation of neutrophil extracellular traps (NETs). HRG KD mice showed severe liver injury with neutrophil infiltration and the formation of NETs. Pretreatment with supplementary HRG protected against I/R with the inhibition of neutrophil infiltration and the formation of NETs. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/reoxygenation conditions, but not in response to oleic acid–treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased farnesoid X receptor and hypoxia inducible factor 2 alpha subunit expression. HRG is a hepatoprotective factor during hepatic IRI because it decreases neutrophil infiltration and the formation of NETs. The decrease in HRG is a cause of susceptibility to IRI in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in patients with NASH.

Distinct inflammatory and transcriptomic profiles in dominant versus subordinate males in mouse social hierarchies

“…Fga (fibrinogen alpha-chain) promotes the synthesis of the alpha portion of fibrinogen and is upregulated in response to tissue injury to help clot formation and induce inflammation (Gabay and Kushner, 1999;Ryu et al, 2015). Hrg is highly connected with the other genes in the module and its protein facilitates blood coagulation, activates lymphocytes and supports healthy liver functioning (Guo et al, 2020;Johnson et al, 2014;Poon et al, 2011). Shifts in the expression of these genes in subordinates with high CORT is likely to occur in response to accumulating injuries in subordinates.…”

Neutrophil subsets in noncancer liver diseases: Cellular crosstalk and therapeutic targets

“…However, steatotic hepatocytes reduce HRG production under hypoxia/reoxygenation conditions, promoting neutrophil activation and NETosis. HRG administration ameliorates hepatic IRI in NASH mouse models by attenuating neutrophil infiltration [81].…”

Neutrophil extracellular traps regulating tumorimmunity in hepatocellular carcinoma

“…Both neutrophils and NETs negatively correlate with the expression of histidine-rich glycoprotein (HRG) in mouse models of liver IRI. Overexpression of HRG in mice suppressed neutrophil infiltration and NET formation in the liver, thus reversing hepatic IRI ( 129 ). Another study demonstrated that hydroxychloroquine inhibits NET formation and alleviates liver IRI in mouse models of liver ischemia-reperfusion ( 48 ).…”