Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

Abstract

The transcription factor nuclear factor-κB (NF-κB) mediates inflammation and stress signals in cells. To test NF-κB in the control of hepatic insulin sensitivity, we inactivated NF-κB in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-κB activity. NF-κB was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-α. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-κB inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

“…35,36 SQSTM1 encodes a multifunctional protein that besides binding ubiquitin and regulating activation of the nuclear factor kappa-B (NF-kB) signaling pathway, has also effects related to impairment of autophagic flux, 37 thereby contributing to hepatic insulin sensitivity. [38][39][40] Moreover, correlations of NASH-associated CpG sites with mRNA expression of CEACAM1, SH3BP4 (encoding transferrin receptor-trafficking protein), and NAT2 also support a role for our findings relating differential DNA methylation in NASH with impaired insulin signaling/action. [41][42][43][44][45][46][47] The mechanisms that could alter DNA methylation in the insulin-resistant liver remain to be elucidated.…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…Moreover, a recent study has shown that hepatic AMPK can phosphorylate and activate PDE4B to suppress glucagon-mediated cAMP/PKA activation (Johanns et al 2016), suggesting that metformin inhibits hepatic PKA via multiple pathways. Another study showed that selective inactivation of NF-κB in mouse liver enhanced insulin sensitivity and suppressed hepatic gluconeogenesis also via inhibition of the cAMP/PKA/CREB pathway (Ke et al 2015). These studies suggest that cAMP/PKA is the major positive regulator for hepatic gluconeogenesis.…”

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

“…Several PDE subtypes and isoforms, including PDE1 [7], PDE3B [8,9], PDE4 [7] and PDE8B [7,10], are known to mediate insulin secretion by pancreatic islets and/or beta cells. Through a feedback mechanism, insulin can reduce intracellular cAMP levels via activation of PDEs either by phosphorylation [11,12] or in the longer term by regulating their protein levels [13,14].…”