Thyroid Hormone-Related Regulation of Gene Expression in Human Fatty Liver
Thyroid Hormone-Related Regulation of Gene Expression in Human Fatty Liver
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DOI：
10.1210/jc.2009-0212
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发表时间：
2009-09-01
影响因子：
5.8
通讯作者：
Patti, Mary Elizabeth
中科院分区：
文献类型：
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作者：
Pihlajamaeki, Jussi;Boes, Tanner;Patti, Mary Elizabeth
背景：脂肪肝是肥胖的一个重要并发症；然而，调节基因表达模式改变的机制尚未确定。目的：该研究的目的是确定人类肝脏中可能导致肝脏脂肪堆积和相关的胰岛素抵抗、2型糖尿病和非酒精性脂肪性肝炎的新的转录变化。设计：我们使用Affymetrix U133A芯片评估了13名肥胖者(9名2型糖尿病患者)和5名对照受试者手术肝活检组织中的基因表达。在另外16名受试者的肝活检中进行了PCR验证。我们还测试了喂食食物或高脂饮食的小鼠的甲状腺激素反应。背景：招募在一个学术医学中心进行。参与者：因肥胖或胆结石而接受择期手术的个体参与了这项研究。结果：在肥胖受试者中下调的顶级基因集由先前证明受人类骨骼肌T-3正调控的基因组成(n=399；P<；0.001；错误发现率=0.07)。该基因包括与RNA代谢(SNRPE、HNRPH3、TIA1和SFRS2)、蛋白质分解代谢(PSMA1、PSMD12、USP9X、IBE2B、Usp16和PCMT1)和能量代谢(ATP5C1、COX7C、UQCRB)相关的基因。我们证实了C57BL/6J小鼠注射T-3(100微克/100克体重)后，肝脏中甲状腺激素对这些基因表达的调节；此外，高脂饮食取消了T-3诱导的这些基因表达的增加。一致认为，这些基因的表达与人类肝脏脂肪含量呈负相关。结论：这些数据表明，甲状腺激素作用受损可能导致脂肪肝基因表达模式的改变。(临床内分泌代谢酶94：3521-3529,2009)
Context: Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified.Objective: The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis.Design: We evaluated gene expression in surgical liver biopsies from 13 obese (nine with type 2 diabetes) and five control subjects using Affymetrix U133A microarrays. PCR validation was performed in liver biopsies using an additional 16 subjects. We also tested thyroid hormone responses in mice fed chow or high-fat diet.Setting: Recruitment was performed in an academic medical center.Participants: Individuals undergoing elective surgery for obesity or gallstones participated in the study.Results: The top-ranking gene set, down-regulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by T-3 in human skeletal muscle (n = 399; P < 0.001; false discovery rate = 0.07). This gene set included genes related to RNA metabolism (SNRPE, HNRPH3, TIA1, and SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, and PCMT1), and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver after injection of C57BL/6J mice with T-3 (100 mu g/100 g body weight); furthermore, T-3-induced increases in expression of these genes were abolished by high-fat diet. In agreement, expression of these genes inversely correlated with liver fat content in humans.Conclusions: These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver. (J Clin Endocrinol Metab 94: 3521-3529, 2009)