Genetic susceptibility to chronic hepatitis is inherited codominantly in Helicobacter hepaticus-infected AB6F1 and B6AF1 hybrid male mice, and progression to hepatocellular carcinoma is linked to hepatic expression of lipogenic genes and immune function-associated networks.
Helicobacter hepaticus causes hepatitis in susceptible strains of mice. Previous studies indicated that A/JCr mice are susceptible and C57BL/6NCr mice are resistant to H. hepaticus-induced hepatitis. We used F1 hybrid mice derived from A/J and C57BL/6 matings to investigate their phenotype and determine their hepatic gene expression profile in response to H. hepaticus infection. F1 hybrid mice, as well as parental A/J and C57BL/6 mice, were divided equally into control and H. hepaticus-infected groups and euthanized at 18 months postinoculation. Hepatic lesions were evaluated histologically and the differential hepatic gene expression in F1 mice was determined by microarray-based global gene expression profiling analysis. H. hepaticus-infected parental strains including A/J and C57BL/6 mice, as well as F1 mice, developed significant hepatitis. Overall, hepatocellular carcinomas or dysplastic liver lesions were observed in 69% of H. hepaticus-infected F1 male mice and H. hepaticus was isolated from hepatic tissues of all F1 mice with liver tumors. Liver tumors, characterized by hepatic steatosis, developed in livers with high hepatitis scores. To identify gene expression specific to H. hepaticus-induced hepatitis and progression to hepatocellular carcinoma in F1 mice, a method using comparative group transcriptome analysis was utilized. The canonical pathway most significantly enriched was immunological disease. Fatty acid synthase and steaoryl-coenzyme A desaturase, the two rate-limiting enzymes in lipogenesis, were upregulated in neoplastic relative to dysplastic livers. This study suggests a synergistic interaction between hepatic steatosis and infectious hepatitis leading to hepatocellular carcinoma. The use of AB6F1 and B6AF1 mice, as well as genetically engineered mice, on a C57BL/6 background will allow studies investigating the role of chronic microbial hepatitis and steatohepatitis in the pathogenesis of liver cancer.
García
Alexis
A
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave. 16-825, Cambridge, MA 02139, USA.
Ihrig
Melanie M
MM
Fry
Rebecca C
RC
Feng
Yan
Y
Xu
Sandy
S
Boutin
Samuel R
SR
Rogers
Arlin B
AB
Muthupalani
Suresh
S
Samson
Leona D
LD
Fox
James G
JG
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D044923:Helicobacter hepaticus / Q000502:physiology; D006521:Hepatitis, Chronic / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D040582:Inheritance Patterns; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D012720:Severity of Illness Index; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis; D015854:Up-Regulation
C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D064429:Fatty Acid Synthases