Hepatocyte-specific deletion of ARNT (aryl hydrocarbon Receptor Nuclear Translocator) results in altered fibrotic gene expression in the thioacetamide model of liver injury.

Abstract

BACKGROUND & AIMS:

Recent studies have shown that increased expression of liver hypoxia inducible factor 2-α (HIF-2α) leads to liver inflammation and a pro-fibrotic gene expression signature. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is required for HIF-2α transcriptional activity and has previously been shown to regulate hepatic metabolism in mice. In these studies we examined the role of hepatocyte ARNT in the thioacetamide (TAA)-induced model of liver fibrosis.

METHODS:

Hepatocyte-specific ARNT-null (LARNT) mice were created using an albumin promoter-driven Cre recombinase. LARNT and floxed control (FC) littermates were placed on chow diet and received twice weekly intraperitoneal injections of 0.15mg/g body weight of TAA for 13 weeks.

RESULTS:

TAA treated LARNT and FC mice had a similar pattern of fibrosis. Quantification of Sirius red histology staining and hydroxyproline content revealed mixed results in terms of collagen deposition in LARNT livers. There was no significant difference in hepatocyte apoptosis or proliferation, as assessed by cleaved Caspase-3 and Ki67 respectively. LARNT mice had decreased macrophage accumulation, and decreased liver mRNA expression of Col1A1, Col1A2, Col5A1, Tgfβ1, Tgfβ2, Timp1 and Timp2.

CONCLUSIONS:

Deletion of hepatocyte ARNT leads to altered expression of collagen associated mRNA and reduced macrophage infiltration in the TAA-induced model of liver fibrosis. It appears that hepatocyte ARNT is not a requirement for initiation of liver fibrogenesis, but does regulate pro-fibrotic gene expression and macrophage accumulation.

• Authors: Christopher Scott, Kuan Cha, Renuka Rao, Christopher Liddle, Jacob George, Jenny E Gunton
• Journal: PloS one (PLoS One) Vol. 10 Issue 3 Pg. e0121650 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25812120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• RNA, Messenger
• Thioacetamide
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Collagen

Topics

• Animals
• Apoptosis
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics)
• Cell Proliferation
• Chemical and Drug Induced Liver Injury (complications, genetics, metabolism, pathology)
• Collagen (metabolism)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Gene Deletion
• Gene Expression Regulation
• Hepatocytes (metabolism)
• Liver Cirrhosis (etiology, pathology)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Knockout
• RNA, Messenger (genetics)
• Thioacetamide (adverse effects)