The 14‐3‐3 protein YWHAB inhibits glucagon‐induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1

Abstract

Glucagon antagonism has been reported as a new therapeutic approach to hyperglycaemia. As the 14‐3‐3 protein YWHAB has been identified as a regulator of the glucagon receptor (GCGR) by affinity purification and mass spectrometry, we examined the role of YWHAB in vivo. Ywhab knockout mice display impaired blood glucose homeostasis only under pyruvate stimulation. Deletion of Ywhab in mouse primary hepatocytes (MPHs) increases hepatocyte glucose production by magnifying the effect of glucagon. Mechanistic analysis indicates that YWHAB forms a phosphorylation‐dependent complex with GCGR and directly interacts with forkhead box O1 (FOXO1). Together, these results reveal the inhibitory role of YWHAB in glucagon‐mediated hepatic glucose production, which may be a potential target for the control of gluconeogenesis and associated metabolic diseases.

Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity

“…YWHAB (14-3-3 protein beta, also known as tyrosine 3-monooxygenase/tryptophan 5monooxygenase activation protein, beta polypeptide) is one of seven isoforms comprising the 14-3-3 proteins. Several studies have shown that YWHAB mediates some obesity-related metabolic pathways, such as insulin signaling, PI3K-AKT-FoxO1 signaling and AMPK signaling, by regulating the activity of its key regulators [47][48][49][50] .…”

Subcutaneous adipose tissue splice quantitative trait loci reveal differences in isoform usage associated with cardiometabolic traits

“…YWHAB is a signaling protein that regulates the glucagon receptor and the loss of Ywhab in mice impaired glucose homeostasis. 49,50 Taken together, the sQTL and exon eQTL, which use different RNA-seq reads, provide stronger evidence of splicing events that correspond to GWAS signals.…”