Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet
Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet
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DOI：
10.1194/jlr.m700222-jlr200
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发表时间：
2007-09-01
影响因子：
6.5
通讯作者：
Horio, Fumihiko
中科院分区：
文献类型：
--
作者：
Kumazawa, Mayumi;Kobayashi, Misato;Horio, Fumihiko
脂肪肝与以肥胖、胰岛素抵抗和2型糖尿病为特征的代谢综合征密切相关，但脂肪肝与代谢综合征的遗传基础和作用机制尚不清楚。SMXA-5小鼠是由SM/J和A/J品系构建的SMXA重组近交系之一，是以中度糖耐量受损、高胰岛素血症和轻度肥胖为特征的多基因2型糖尿病模型。SMXA-5小鼠也患上了脂肪肝，高脂饮食明显恶化了这一特征，尽管SM/J和A/J小鼠在高脂饮食下对脂肪肝的发展具有抵抗力。为了剖析SMXA-5基因组A/J区脂肪肝的基因座，我们尝试对饲喂高脂饲料的(SM/J×SMXA-5)F2杂交小鼠进行数量性状基因座(QTL)分析。我们在12号染色体D12Mit270附近定位了一个控制相对肝重和肝脂含量的主效QTL，命名为Fl1sa。该基因座的A/J等位基因对这些性状的增加有贡献。我们用A/J-Chr12(SM)共体株证实了Fl1sa对肝脏脂质蓄积的影响，其蓄积量明显低于A/J小鼠。这表明SM/J和A/J两株都不会发生脂肪肝，它们都有导致脂肪肝的基因座，这些基因座的共存导致了SMXA-5小鼠脂肪肝。
Fatty liver is strongly associated with the metabolic syndrome characterized by obesity, insulin resistance, and type 2 diabetes, but the genetic basis and functional mechanisms linking fatty liver with the metabolic syndrome are largely unknown. The SMXA-5 mouse is one of the SMXA recombinant inbred substrains established from SM/J and A/J strains and is a model for polygenic type 2 diabetes, characterized by moderately impaired glucose tolerance, hyperinsulinemia, and mild obesity. SMXA-5 mice also developed fatty liver, and a high-fat diet markedly worsened this trait, although SM/J and A/J mice are resistant to fatty liver development under a high-fat diet. To dissect loci for fatty liver in the A/J regions of the SMXA-5 genome, we attempted quantitative trait loci (QTLs) analysis in (SM/J x SMXA-5) F2 intercross mice fed a high-fat diet. We mapped a major QTL for relative liver weight and liver lipid content near D12Mit270 on chromosome 12 and designated this QTL Fl1sa. The A/J allele at this locus contributes to the increase in these traits. We confirmed the effect of Fl1sa on lipid accumulation in liver using the A/J-Chr12(SM) consomic strain, which showed significantly less accumulation than A/J mice. This suggests that the SM/J and A/J strains, neither of which develops fatty liver, possess loci causing fatty liver and that the coexistence of these loci causes fatty liver in SMXA-5 mice.