FAM3D inhibits gluconeogenesis in high glucose environment via DUSP1/ZFP36/SIK1 axis

Abstract

Hyperglycemia is the most important factor leading to the complications of type 2 diabetes mellitus (T2DM). The primary condition for the treatment of T2DM is to change the glucose and lipid metabolism disorders in the liver and other insulin-sensitive tissues. The current study aims to unearth the potential molecular mechanism of inhibiting liver gluconeogenesis to provide a new theoretical basis for the treatment of T2DM. High glucose (HG) induction of HepG2 cells followed by treatment with sequence-similar family 3 member D (FAM3D). Dual specificity phosphatases 1 (DUSP1), zinc finger protein 36 (ZFP36), salt-induced kinase 1 (SIK1), p-SIK1, posphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene and protein expression level were detected by quantitative real-time polymerase chain reaction and western blot. The PEPCK and G6Pase activities were detected by enzyme linked immunosorbent assay.Glucose production assay to determine glucose content. The RNA binding protein immunoprecipitation assay was used to detect the binding of ZFP36 to SIK1. FAM3D facilitated the expression of DUSP1 but suppressed the expression of gluconeogenesis-related factors in an HG environment. The expression of ZFP36 was up-regulated in an HG environment. ZFP36 could reverse the inhibition of gluconeogenesis caused by FAM3D. HG-induced upregulation of ZFP36 was downregulated by overexpression of DUSP1. ZFP36 bound to SIK1, and downregulation of ZFP36 promoted SIK1 expression and inhibits gluconeogenesis. Our study demonstrated FAM3D inhibited gluconeogenesis through the DUSP1/ ZFP36/SIK1 axis in an HG environment, which provided a new theoretical basis for exploring the pathogenesis and treatment strategy of T2DM.

Integrated bioinformatics analyses identifying potential biomarkers for type 2 diabetes mellitus and breast cancer: In SIK1-ness and health

“…To comprehend their roles in T2DM-BC crosstalk, it is essential to understand the currently known contributions of these additional key genes identified by validation study, to the combinatorial and differential T2DM and BC associated signaling pathways. In continuation with previous discussion on SIK1, as depicted in Fig 10, and as supported by pathway enrichment analysis, it is implicated in fasting/hyperglycemia induced silencing of genes responsible for gluconeogenesis [58,59]. It is also reported as a potentially promising therapeutic target for countering insulin resistance in obesity [60].…”

Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms

“…[25][26][27] Activation of DUSP1 has been shown to inhibit gluconeogenesis, suppress glycolipid metabolism, and reduce lipid accumulation. [28] IKZF3, a member of the zinc-finger protein family of transcription factors, is crucial for the development and differentiation of lymphocytes. [29] However, its role in NASH has not yet been reported, suggesting that IKZF3 may represent a novel target for the treatment or diagnosis of NASH.…”