Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
Junior Group Cellular Senescence, DKFZ, 69120 Heidelberg, Germany.
Mol Metab. 2014 Jan 8;3(2):155-66. doi: 10.1016/j.molmet.2013.12.007. eCollection 2014 Apr.
Disturbances in lipid homeostasis are hallmarks of severe metabolic disorders and their long-term complications, including obesity, diabetes, and atherosclerosis. Whereas elevation of triglyceride (TG)-rich very-low-density lipoproteins (VLDL) has been identified as a risk factor for cardiovascular complications, high-density lipoprotein (HDL)-associated cholesterol confers atheroprotection under obese and/or diabetic conditions. Here we show that hepatocyte-specific deficiency of transcription factor transforming growth factor β 1-stimulated clone (TSC) 22 D1 led to a substantial reduction in HDL levels in both wild-type and obese mice, mediated through the transcriptional down-regulation of the HDL formation pathway in liver. Indeed, overexpression of TSC22D1 promoted high levels of HDL cholesterol in healthy animals, and hepatic expression of TSC22D1 was found to be aberrantly regulated in disease models of opposing energy availability. The hepatic TSC22D1 transcription factor complex may thus represent an attractive target in HDL raising strategies in obesity/diabetes-related dyslipidemia and atheroprotection.
脂质代谢稳态紊乱是严重代谢紊乱及其长期并发症的特征，包括肥胖、糖尿病和动脉粥样硬化。虽然富含甘油三酯（TG）的极低密度脂蛋白（VLDL）的升高已被确定为心血管并发症的危险因素，但高密度脂蛋白（HDL）相关胆固醇在肥胖和/或糖尿病情况下具有抗动脉粥样硬化作用。在这里，我们发现，转录因子转化生长因子β 1 刺激克隆（TSC）22D1 的肝细胞特异性缺失导致野生型和肥胖小鼠的 HDL 水平显著降低，这是通过肝脏中 HDL 形成途径的转录下调介导的。事实上，TSC22D1 的过表达促进了健康动物中 HDL 胆固醇的高水平，并且在能量利用相反的疾病模型中发现肝内 TSC22D1 的表达异常调节。因此，肝 TSC22D1 转录因子复合物可能成为肥胖/糖尿病相关血脂异常和抗动脉粥样硬化中升高 HDL 的有吸引力的靶点。
