Role of transcription factor modifications in the pathogenesis of insulin resistance

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver not due to alcohol abuse. NAFLD is accompanied by variety of symptoms related to metabolic syndrome. Although the metabolic link between NAFLD and insulin resistance is not fully understood, it is clear that NAFLD is one of the main cause of insulin resistance. NAFLD is shown to affect the functions of other organs, including pancreas, adipose tissue, muscle and inflammatory systems. Currently efforts are being made to understand molecular mechanism of interrelationship between NAFLD and insulin resistance at the transcriptional level with specific focus on post-translational modification (PTM) of transcription factors. PTM of transcription factors plays a key role in controlling numerous biological events, including cellular energy metabolism, cell-cycle progression, and organ development. Cell type- and tissue-specific reversible modifications include lysine acetylation, methylation, ubiquitination, and SUMOylation. Moreover, phosphorylation and O-GlcNAcylation on serine and threonine residues have been shown to affect protein stability, subcellular distribution, DNA-binding affinity, and transcriptional activity. PTMs of transcription factors involved in insulin-sensitive tissues confer specific adaptive mechanisms in response to internal or external stimuli. Our understanding of the interplay between these modifications and their effects on transcriptional regulation is growing. Here, we summarize the diverse roles of PTMs in insulin-sensitive tissues and their involvement in the pathogenesis of insulin resistance.

Figure 1

The types and functions of post-translational modification of transcription factors.

Figure 2

Post-translational modifications (PTMs) of transcription factors. (a) The positions of PTM sites in the human FOXO1, SREBP-1c, and NF-κB p65 subunit.The positions of PTM sites and the implicated modifying enzymes are shown. (+) and (–) represent activation and inhibition of the transcriptional activity of transcription factors, respectively. L1-2, nuclear localization sequences; E1-3, nuclear export sequences; DBD, DNA-binding domain; TAD, transactivation domain; RHD, Rel homology domain; NLS, nuclear localization sequence; TAD, transactivation domain. (b) Regulation of FOXO1 nucleocytoplasmic shuttling and transcriptional activity by PTMs in liver. (c) Regulation of transcription factor activities by PTMs in pancreatic β cells. P, phosphate group; Ac, acetyl group; G, O-linked-N-acetylglucosamine; Ub, ubiquitin; S, SUMO; Akt, v-akt murine thymoma viral oncogene homolog 1 (also known as protein kinase B [PKB]); SGK, serum/glucocorticoid-regulated kinase; CK1, casein kinase 1; DYRK1A, dual-specificity tyrosine-phosphorylated and regulated kinase1 A; CDK2, cyclin-dependent kinase 2. PI3K, phosphoinositide-3-kinase; PDK, phosphatidylinositol-dependent protein kinase; OGT, O-linked N-acetylglucosamine (GlcNAc) transferase; MAPK1/3, mitogen-activated protein kinase 1/3; Ubc9, ubiquitin conjugating enzyme 9; p300, E1A-binding protein p300; CBP, CREB-binding protein; SIRT1, sirtuin 1; PKA, protein kinase A; cAMP, cyclic adenosine monophosphate; SIK, salt-inducible kinase; GSK-3, glycogen synthase kinase-3; JNK, c-Jun N-terminal kinase; PCAF, CBP/p300-associated factor; MSK1, mitogen/stress-activated protein kinase 1; PKCζ, protein kinase Cζ; IKK, I kappa B kinase; CK2, casein kinase 2; TBK1, tank-binding kinase 1; SOCS-1, suppressor of cytokine signaling 1; HBP, hexosamine biosynthesis pathway; OGA, O-GlcNAcase; PDX1, pancreatic and duodenal homeobox 1; NeuroD, neurogenic differentiation; MafA, v-maf (maf musculoaponeurotic fibrosarcoma) oncogene homolog A.