Introduction: Non-alcoholic fatty liver disease is the most common hepatic disorder in Western countries. The transition from abnormal accumulation of lipids toward non-alcoholic steatohepatitis (NASH) represents a key step in the development of chronic liver pathologies. Oxidative stress and lipid peroxidation have often been proposed as mechanisms in the progression to steatohepatitis. Methods: We have examined the hepatic levels of exocyclic DNA adducts, indicated from 3-(2-deoxy-β-Derythro- pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG) adduct, a biomarker of oxidative stress and lipid peroxidation, in a murine model of NASH using the 32P-DNA postlabeling assay. Results: Our findings show that C57BL/6 mice fed with high-fat and cholesterol diet developed signs associated with NASH after eight weeks, whereas there was no evidence of steatosis in control mice. The score for steatohepatitis ranged from grade 2 to 3 for steatosis, inflammation, and fibrosis, showing that the experimental diet was able to induce pathologic alterations of the parenchyma in eight weeks. Higher levels of M1dG adducts were detected in the livers of C57BL/6 mice which developed experimental NASH after eight weeks of high-fat and cholesterol feed, 5.6 M1dG ± 0.4 (SE) per 106 total nucleotides, as compared to control mice, 1.6 M1dG ± 0.4 (SE). The statistical analysis showed that the increment of oxidatively damaged DNA in mice with NASH raised on high-fat and cholesterol diet was statistically significant as compared to control mice, P=0.006. Conclusions: Our report suggests a link between NASH and M1dG in experimental animals fed with a diet rich in saturated fats and cholesterol. High-fat and cholesterol may act together in inducing a broader spectrum of oxidatively damaged DNA, including exocyclic DNA adducts, that may contribute to the decline of hepatocyte functions, from disturbance of critical pathways, such as transcription and replication, triggering transient or permanent cell-cycle arrest and cell-death, up to chromosomal instability.

Exocycilic DNA Adducts in a Murine Model of Non-alcoholic Steatohepatitis / Peluso, Marco E M; Munnia, Armelle; Tarocchi, Mirko; Arciello, Mario; Balsano, Clara; Giese, Roger W; Galli, Andrea. - In: JOURNAL OF CARCINOGENESIS & MUTAGENESIS. - ISSN 2157-2518. - ELETTRONICO. - (2013), pp. 1-7. [10.4172/2157-2518.S3-003]

Exocycilic DNA Adducts in a Murine Model of Non-alcoholic Steatohepatitis

TAROCCHI, MIRKO;GALLI, ANDREA
2013

Abstract

Introduction: Non-alcoholic fatty liver disease is the most common hepatic disorder in Western countries. The transition from abnormal accumulation of lipids toward non-alcoholic steatohepatitis (NASH) represents a key step in the development of chronic liver pathologies. Oxidative stress and lipid peroxidation have often been proposed as mechanisms in the progression to steatohepatitis. Methods: We have examined the hepatic levels of exocyclic DNA adducts, indicated from 3-(2-deoxy-β-Derythro- pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG) adduct, a biomarker of oxidative stress and lipid peroxidation, in a murine model of NASH using the 32P-DNA postlabeling assay. Results: Our findings show that C57BL/6 mice fed with high-fat and cholesterol diet developed signs associated with NASH after eight weeks, whereas there was no evidence of steatosis in control mice. The score for steatohepatitis ranged from grade 2 to 3 for steatosis, inflammation, and fibrosis, showing that the experimental diet was able to induce pathologic alterations of the parenchyma in eight weeks. Higher levels of M1dG adducts were detected in the livers of C57BL/6 mice which developed experimental NASH after eight weeks of high-fat and cholesterol feed, 5.6 M1dG ± 0.4 (SE) per 106 total nucleotides, as compared to control mice, 1.6 M1dG ± 0.4 (SE). The statistical analysis showed that the increment of oxidatively damaged DNA in mice with NASH raised on high-fat and cholesterol diet was statistically significant as compared to control mice, P=0.006. Conclusions: Our report suggests a link between NASH and M1dG in experimental animals fed with a diet rich in saturated fats and cholesterol. High-fat and cholesterol may act together in inducing a broader spectrum of oxidatively damaged DNA, including exocyclic DNA adducts, that may contribute to the decline of hepatocyte functions, from disturbance of critical pathways, such as transcription and replication, triggering transient or permanent cell-cycle arrest and cell-death, up to chromosomal instability.
2013
1
7
Peluso, Marco E M; Munnia, Armelle; Tarocchi, Mirko; Arciello, Mario; Balsano, Clara; Giese, Roger W; Galli, Andrea
File in questo prodotto:
File Dimensione Formato  
exocycilic-dna-adducts-in-a-murine-model-of-nonalcoholic-steatohepatitis-2157-2518-S3-003.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 838.36 kB
Formato Adobe PDF
838.36 kB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1015678
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact