Hepatic Deficiency in Transcriptional Cofactor TBL1 Promotes Liver Steatosis and Hypertriglyceridemia
Hepatic Deficiency in Transcriptional Cofactor TBL1 Promotes Liver Steatosis and Hypertriglyceridemia
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DOI：
10.1016/j.cmet.2011.02.011
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发表时间：
2011-04-06
期刊：
影响因子：
29
通讯作者：
Herzig, Stephan
中科院分区：
文献类型：
--
作者：
Kulozik, Philipp;Jones, Allan;Herzig, Stephan
肝脏中脂质的异常积累（“脂肪肝”）与代谢综合征的几个组成部分密切相关，包括2型糖尿病、冠心病和动脉粥样硬化。在这里，我们表明，转录辅因子转导β样（TBL）1的肝脏表达受损代表了单基因和多基因脂肪肝小鼠模型的共同特征。事实上，在正常和高脂肪饮食条件下，健康小鼠中TBL 1基因表达的肝脏特异性消融促进了高脂血症和肝脏脂肪变性。TBL 1缺陷导致脂肪酸氧化的抑制，这是由于与其异源二聚化伴侣TBLR 1和核受体过氧化物酶体增殖物激活受体（PPAR）a的功能合作受损。由于发现TBL 1表达水平也与人类患者的肝脏脂肪含量呈负相关，因此肝脏TBL 1/TBLR 1辅因子活性的缺乏可能代表肥胖和代谢综合征受试者肝脏脂肪变性的分子基础。
The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) a. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.