TEAD1, MYO7A and NDUFC2 are novel functional genes associated with glucose metabolism in BXD recombinant inbred population

Aim: The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause non-alcoholic fatty liver disease, type 2 diabetes mellitus, dyslipidaemia, etc. We aimed use systematic investigation of the key factors related to hepatic glucose metabolism, which may be beneficial for understanding the underlying pathogenic mechanisms for obesity and diabetes mellitus. Materials and methods: Oral glucose tolerance test (OGTT) phenotypes and liver transcriptomes of BXD mice under chow and high-fat diet conditions were collected from GeneNetwork. QTL mapping was conducted to pinpoint genomic regions associated with glucose homeostasis. Candidate genes were further nominated using a multi-criteria approach and in vitro validated to confirm their functional relevance. Results; Our results showed that plasma glucose levels in the oral glucose tolerance test were significantly affected by both diet and genetic background. To identify further the candidate genes associated with hepatic glucose metabolism, the results revealed nine genetic regulating loci on chromosomes 1, 4, 7 and 11, respectively, by quantitative trait loci mapping. Moreover, TEA Domain Transcription Factor 1 (TEAD1), myosin VIIA (MYO7A) and NADH:ubiquinone oxidoreductase subunit C2 (NDUFC2) were identified as the candidate functional genes. Functionally, siRNA-mediated TEAD1, MYO7A and NDUFC2 significantly decreased glucose uptake. Reverse transcription-polymerase chain reaction assays confirmed that the downregulation of those three candidates inhibited the transcription of genes related to insulin and glucose metabolism pathways. Conclusions: Our study contributes novel insights to the understanding of hepatic glucose metabolish, demonstrating the impact of TEAD1, MYO7A and NDUFC2 on mitochondrial function in the liver and their regulatory role in maintaining in glucose homeostasis.