OBESITY-INDUCED DIABETES (DIABESITY) IN C57BL/KSJ MICE PRODUCES ABERRANT TRANSREGULATION OF SEX STEROID SULFOTRANSFERASE GENES
OBESITY-INDUCED DIABETES (DIABESITY) IN C57BL/KSJ MICE PRODUCES ABERRANT TRANSREGULATION OF SEX STEROID SULFOTRANSFERASE GENES
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DOI：
10.1172/jci117194
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发表时间：
1994-05-01
影响因子：
15.9
通讯作者：
CHAPMAN, HD
中科院分区：
文献类型：
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作者：
LEITER, EH;CHAPMAN, HD
糖尿病（db）基因是小鼠中的隐性肥胖突变，其仅能够通过与某些近交系的遗传背景中迄今未定义的修饰物相互作用而产生糖尿病。在这里，我们确定了雄激素和雌激素磺基转移酶基因的遗传图谱位置，这些基因对维持肝脏中活性性类固醇的平衡很重要。编码脱氢表雄酮磺基转移酶的Std基因座定位于近端7号染色体，编码雌激素磺基转移酶的Ste基因座定位于5号染色体。在糖尿病易感的C57 BL/KsJ株中的db突变异常调节来自这两个位点的mRNA转录水平。肝Ste mRNA转录物从正常雄性和雌性小鼠中的不可检测水平增加到两种性别的db/db小鼠中的高水平。在db/db雌性动物中观察到Std转录的异常抑制，但在正常雌性动物中未观察到。这些相互变化的突变体女性的mRNA浓度反映了诱导的高亲和力雌激素磺基转移酶活性和随之而来的损失脱氢表雄酮磺基转移酶活性。这些db基因引起的效应对性类固醇磺基转移酶具有特异性，因为其他潜在的性类固醇代谢酶（苯酚磺基转移酶、性类固醇磺基水解酶和UDP-葡糖醛酸转移酶）不受影响。这些异常变化将通过增加活性雄激素与雌激素的比例来抑制雌性动物的肝脏代谢。在人类女性中，当内脏肥胖和高胰岛素血症与高雄激素化相关时，通常会发生非胰岛素依赖型糖尿病。这项研究表明，背景修饰基因与肥胖突变有害地相互作用，不一定是有缺陷的等位基因。相反，一些是功能基因，其调节已被肥胖基因的多效性效应改变。
The diabetes (db) gene is a recessive obesity mutation in the mouse capable of producing diabetes only through interaction with heretofore undefined modifiers in the genetic background of certain inbred strains. Here we identify the genetic map locations of androgen and estrogen sulfotransferase genes important in maintaining the balance of active sex steroids in the liver. The Std locus encoding dehydroepiandrosterone sulfotransferase was mapped to proximal Chromosome 7, and the Ste locus encoding estrogen sulfotransferase was mapped to Chromosome 5. The db mutation in the diabetes-susceptible C57BL/KsJ strain aberrantly regulated mRNA transcript levels from these two loci. Hepatic Ste mRNA transcripts were increased from undetectable levels in normal males and females to high levels in db/db mice of both sexes. An anomalous suppression of Std transcription was observed in db/db females, but not in normal females. These reciprocal changes in mRNA concentrations in mutant females were reflected by an induction of a high affinity estrogen sulfotransferase activity and a concomitant loss of dehydroepiandrosterone sulfotransferase activity. These db gene-elicited effects were specific for the sex steroid sulfotransferases since other potential sex steroid metabolizing enzymes (phenol sulfotransferase, sex steroid sulfohydrolase, and UDP-glucuronyltransferase) were unaffected. These aberrant changes would virilize hepatic metabolism in females by increasing the ratio of active androgens to estrogens. In human females, non-insulin-dependent diabetes mellitus often develops when visceral obesity and hyperinsulinemia are associated with hyperandrogenization. This study demonstrates that background modifier genes interacting deleteriously with an obesity mutation are not necessarily defective alleles. Rather, some are functional genes whose regulation has been altered by pleiotropic effects of the obesity gene.