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Detection of differentially expressed candidate genes for a fatty liver QTL on mouse chromosome 12

Kobayashi, Misato, Suzuki, Miyako, Ohno, Tamio, Tsuzuki, Kana, Taguchi, Chie, Tateishi, Soushi, Kawada, Teruo, Kim, Young-il, Murai, Atsushi, Horio, Fumihiko
BMC genetics 2016 v.17 no.1 pp. 73
DNA microarrays, alleles, animal models, chromosomes, esterases, fatty liver, gene overexpression, hepatoma, high fat diet, kidneys, lipid metabolism, liver, messenger RNA, mice, microarray technology, quantitative trait loci, triacylglycerols
BACKGROUND: The SMXA-5 mouse is an animal model of high-fat diet-induced fatty liver. The major QTL for fatty liver, Fl1sa on chromosome 12, was identified in a SM/J × SMXA-5 intercross. The SMXA-5 genome consists of the SM/J and A/J genomes, and the A/J allele of Fl1sa is a fatty liver-susceptibility allele. The existence of the responsible genes for fatty liver within Fl1sa was confirmed in A/J-12Sᴹ consomic mice. The aim of this study was to identify candidate genes for Fl1sa, and to investigate whether the identified genes affect the lipid metabolism. RESULTS: A/J-12Sᴹ mice showed a significantly lower liver triglyceride content compared to A/J mice when fed the high-fat diet for 7 weeks. We detected differences in the accumulation of liver lipids in response to the high-fat diet between A/J and A/J-12Sᴹ consomic mice. To identify candidate genes for Fl1sa, we performed DNA microarray analysis using the livers of A/J-12Sᴹ and A/J mice fed the high-fat diet. The mRNA levels of three genes (Iah1, Rrm2, Prkd1) in the chromosomal region of Fl1sa were significantly different between the strains. Iah1 mRNA levels in the liver, kidney, and lung were significantly higher in A/J-12Sᴹ mice than in A/J mice. The hepatic Iah1 mRNA level in A/J-12Sᴹ mice was 3.2-fold higher than that in A/J mice. To examine the effect of Iah1 on hepatic lipid metabolism, we constructed a stable cell line expressing the mouse Iah1 protein in mouse hepatoma Hepa1-6 cells. Overexpression of Iah1 in Hepa1-6 cells suppressed the mRNA levels of Cd36 and Dgat2, which play important roles in triglyceride synthesis and lipid metabolism. CONCLUSIONS: These results demonstrated that Fl1sa on the proximal region of chromosome 12 affected fatty liver in mice on a high-fat diet. Iah1 (isoamyl acetate-hydrolyzing esterase 1 homolog) was identified as one of the candidate genes for Fl1sa. This study revealed that the mouse Iah1 gene regulated the expression of genes related to lipid metabolism in the liver.