Lin Xin, Liou Yae-Huei, Li Yujun, Gong Lu, Li Yan, Hao Yuan, Pham Betty, Xu Shuang, Jiang Zhiqiang, Li Lijia, Peng Yifan, Qiao Dandi, Lin Honghuang, Liu Pengda, Wei Wenyi, Zhang Guo, Lee Chih-Hao, Zhou Xiaobo
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
iScience. 2020 Mar 27;23(3):100928. doi: 10.1016/j.isci.2020.100928. Epub 2020 Feb 22.
Obesity commonly co-exists with fatty liver disease with increasing health burden worldwide. Family with Sequence Similarity 13, Member A (FAM13A) has been associated with lipid levels and fat mass by genome-wide association studies (GWAS). However, the function of FAM13A in maintaining metabolic homeostasis in vivo remains unclear. Here, we demonstrated that rs2276936 in this locus has allelic-enhancer activity in massively parallel reporter assays (MPRA) and reporter assay. The DNA region containing rs2276936 regulates expression of endogenous FAM13A in HepG2 cells. In vivo, Fam13a mice are protected from high-fat diet (HFD)-induced fatty liver accompanied by increased insulin sensitivity and reduced glucose production in liver. Mechanistically, loss of Fam13a led to the activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes. These findings demonstrate that FAM13A mediates obesity-related dysregulation of lipid and glucose homeostasis. Targeting FAM13A might be a promising treatment of obesity and fatty liver disease.
肥胖通常与脂肪性肝病并存，在全球范围内给健康带来越来越大的负担。全基因组关联研究（GWAS）表明，序列相似性家族13成员A（FAM13A）与血脂水平和脂肪量有关。然而，FAM13A在体内维持代谢稳态中的功能仍不清楚。在此，我们证明了该基因座中的rs2276936在大规模平行报告基因检测（MPRA）和报告基因检测中具有等位基因增强活性。包含rs2276936的DNA区域调节HepG2细胞中内源性FAM13A的表达。在体内，Fam13a基因敲除小鼠可免受高脂饮食（HFD）诱导的脂肪肝影响，同时肝脏胰岛素敏感性增加，葡萄糖生成减少。机制上，Fam13a基因缺失导致原代肝细胞中AMP激活的蛋白激酶（AMPK）活化，线粒体呼吸增加。这些发现表明，FAM13A介导肥胖相关的脂质和葡萄糖稳态失调。靶向FAM13A可能是治疗肥胖和脂肪性肝病的一种有前景的方法。
