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, Heidelberg, Germany.
EMBO Mol Med. 2013 Feb;5(2):294-308. doi: 10.1002/emmm.201201869. Epub 2013 Jan 11.
In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very-low-density-lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1-stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver-specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo-secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell-induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.
在哺乳动物中，组织内和组织间脂质的适当储存和分布对于维持能量平衡至关重要。在这里，我们表明肿瘤生长会引发肝代谢功能障碍，这是癌症恶病质表型的一部分，特别是通过降低肝极低密度脂蛋白 (VLDL) 的分泌和低β脂蛋白血症。作为分子恶病质输出途径，肿瘤恶病质中肝转录因子转化生长因子 β 1 刺激克隆 (TSC) 22D4 的水平增加。在健康肝脏中模拟高恶病质水平的 TSC22D4 会导致肝 VLDL 释放和生脂基因受到抑制，并在正常和高脂肪饮食条件下降低系统 VLDL 水平。肝特异性敲除 TSC22D4 通过诱导肝 VLDL 分泌引发高甘油三酯血症。此外，肝 TSC22D4 表达水平与癌症恶病质中体重减轻的程度和 VLDL 分泌不足相关，并且 TSC22D4 缺乏可挽救肿瘤细胞诱导的肝细胞代谢功能障碍。因此，肝 TSC22D4 活性可能代表包括癌症恶病质在内的代谢消耗性疾病中外周能量消耗的分子基础。
