Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3277-3285. doi: 10.1016/j.bbadis.2017.09.021. Epub 2017 Sep 28.
The transcription factor Krüppel-like factor 14 (KLF14) has been associated with type 2 diabetes and high-density lipoprotein-cholesterol (HDL-C) through genome-wide association studies. The mechanistic underpinnings of KLF14's control of metabolic processes remain largely unknown. We studied the physiological roles of KLF14 in a knockout (KO) mouse model.
Male whole body Klf14 KO mice were fed a chow or high fat diet (HFD) and diet induced phenotypes were analyzed. Additionally, tissue-specific expression of Klf14 was determined using RT-PCR, RNA sequencing, immunoblotting and whole mount lacZ staining. Finally, the consequences of KLF14 loss-of-function were studied using RNA sequencing in tissues with relatively high Klf14 expression levels.
KLF14 loss-of-function did not affect HFD-induced weight gain or insulin resistance. Fasting plasma concentrations of glucose, insulin, cholesterol, HDL-C and ApoA-I were also comparable between Klf14 and Klf14 mice on chow and HFD. We found that in mice expression of Klf14 was the highest in the anterior pituitary (adenohypophysis), lower but detectable in white adipose tissue and undetectable in liver. Loss of KLF14 function impacted on the pituitary transcriptome with extracellular matrix organization as the primary affected pathway and a predicted link to glucocorticoid receptor signaling.
Whole body loss of KLF14 function in male mice does not result in metabolic abnormalities as assessed under chow and HFD conditions. Mostly likely there is redundancy for the role of KLF14 in the mouse and a diverging function in humans.
转录因子 Krüppel 样因子 14（KLF14）已通过全基因组关联研究与 2 型糖尿病和高密度脂蛋白胆固醇（HDL-C）相关。KLF14 控制代谢过程的机制基础在很大程度上仍然未知。我们在敲除（KO）小鼠模型中研究了 KLF14 的生理作用。
雄性全身 Klf14 KO 小鼠喂食标准或高脂肪饮食（HFD），并分析饮食诱导的表型。此外，使用 RT-PCR、RNA 测序、免疫印迹和全组织β半乳糖苷酶染色来确定 Klf14 的组织特异性表达。最后，使用相对高表达 Klf14 的组织中的 RNA 测序研究了 KLF14 功能丧失的后果。
KLF14 功能丧失不影响 HFD 诱导的体重增加或胰岛素抵抗。禁食血浆葡萄糖、胰岛素、胆固醇、HDL-C 和 ApoA-I 浓度在 Klf14 和 Klf14 小鼠的标准饮食和 HFD 之间也相似。我们发现，在小鼠中，Klf14 的表达在垂体前叶（腺垂体）中最高，在白色脂肪组织中较低但可检测，在肝脏中不可检测。KLF14 功能丧失会影响垂体转录组，其中细胞外基质组织作为主要受影响途径，预测与糖皮质激素受体信号有关。
雄性小鼠全身缺失 KLF14 功能不会导致在标准饮食和 HFD 条件下评估的代谢异常。很可能 KLF14 在小鼠中的作用存在冗余，而在人类中则存在不同的功能。
