iScience
Volume 23, Issue 3, 27 March 2020, 100928
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Article
FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism

https://doi.org/10.1016/j.isci.2020.100928Get rights and content
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Highlights

  • 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 activity

Summary

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.

Subject Areas

Biological Sciences
Cell Biology
Functional Aspects of Cell Biology

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