Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis

Front Immunol. 2024 Feb 26:15:1342404. doi: 10.3389/fimmu.2024.1342404. eCollection 2024.

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%-30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development.

Methods: The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG-/- mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC.

Results: In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG-/- mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1β, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients.

Conclusion: Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.

Keywords: HCC; MASH; chronic liver diseases; fibrogenesis; hepatocellular carcinoma; histidine-rich glycoprotein; inflammation; liver carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides*
  • Animals
  • Carcinogenesis
  • Carcinoma, Hepatocellular* / etiology
  • Disease Progression
  • Humans
  • Liver Cirrhosis / etiology
  • Liver Neoplasms* / etiology
  • Metabolic Diseases*
  • Mice
  • Non-alcoholic Fatty Liver Disease*
  • Proteins*

Substances

  • histidine-rich proteins
  • CDAA
  • Acetamides
  • Proteins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The research leading to these results has received funding from: i) AIRC under IG 2017 Id. 20361 project – P.I. Parola Maurizio; ii) European Union’s Horizon 2020 research and innovation program under grant agreement No. 634413 for the project EPoS (Elucidating Pathways of Steatohepatitis) (to EB); iii) The University of Torino (Torino, Italy), (to EN and MP); The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.