摘要：SummaryObesity 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 homeostasisin vivoremains 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.Graphical AbstractDisplay OmittedHighlights•SNP rs2276936 regulates expression of endogenous FAM13A•Fam13a−/−mice are protected from high-fat-diet-induced obesity and fatty liver.•Fam13a−/−hepatocytes show increased mitochondrial respiration and AMPK activityBiological Sciences; Cell Biology; Functional Aspects of Cell Biology
