Krüppel-like factors: Crippling and un-crippling metabolic pathways

Abstract

Krüppel-like factors (KLFs) are DNA-binding transcriptional factors that regulate various pathways that control metabolism and other cellular mechanisms. Various KLF isoforms have been associated with cellular, organ or systemic metabolism. Altered expression or activation of KLFs has been linked to metabolic abnormalities, such as obesity and diabetes, as well as with heart failure. In this review article we summarize the metabolic functions of KLFs, as well as the networks of different KLF isoforms that jointly regulate metabolism in health and disease.

Keywords: Krüppel-like factors; diabetes; heart failure; metabolism; obesity.

Graphical abstract

Figure 1

Transcriptional Coregulators of KLF Isoforms KLF isoforms can be divided into 3 groups based on their interaction motifs for transcriptional co-activators and co-repressors. Group 1 includes KLFs which contain the CtBP binding motif. Group 2 includes KLFs which contain the Sin3A interaction domain. Group 3 includes KLFs which interact with acetyl-transferases. KLF = Krüppel-like factor; CBP = cAMP response element binding protein; CtBP = C-terminal binding protein; HDAC = deacetylases; NF-κB = nuclear factor–κB; P/CAF = p300/CBP-associated factor; PGC-1 = PPARγ coactivator 1.

Figure 2

KLF Isoforms Associated With Cardiac Lipid Metabolism Summary of KLF isoforms and metabolic pathways involved in cardiomyocyte biology. A detailed description of the pathways involved in included in the text. Figure was produced using Servier Medical Art (http://www.servier.com/). BCAA = branched chain amino acid; ERR = estrogen-related receptor; KLF = Krüppel-like factor; PPAR = peroxisome proliferator-activated receptor; other abbreviations as in Figure 1.

Figure 3

KLF Isoforms That Control Metabolism in Skeletal Muscles Summary of KLF isoforms and metabolic pathways involved in skeletal muscle biology. A detailed description of the pathways involved in included in the text. Figure was produced using Servier Medical Art (http://www.servier.com/). GLUT4 = glucose transporter type 4; other abbreviations as in Figures 1 and 2.

Figure 4

KLF Isoforms That Control Adipocyte Differentiation Summary of KLF isoforms and metabolic pathways involved in adipocyte biology. A detailed description of the pathways involved in included in the text. Figure was produced using Servier Medical Art (http://www.servier.com/). C/EBP = CCAAT/enhancer-binding protein; Dlk1 = delta-like noncanonical notch ligand 1; other abbreviations as in Figures 1 and 2.

Figure 5

KLF Isoforms That Control Hepatic Metabolism Summary of KLF isoforms and metabolic pathways involved in hepatocyte biology. A detailed description of the pathways involved in included in the text. Figure was produced using Servier Medical Art (http://www.servier.com/). CD = cluster of differentiation; FA = fatty acid; PEPCK = phosphoenolpyruvate carboxykinase; TGFβ = transforming growth factor beta; other abbreviations as in Figures 1 and 2.

Figure 6

KLF Isoforms Associated With the Development of Cardiac Hypertrophy and Dilated Cardiomyopathy and Fibrosis Green indicates protective effect, and red indicates aggravating effect. The (+) sign indicates Krüppel-like factor (KLF) isoforms that promote the phenotype described next to the organs. The (-) sign indicates alleviation of the phenotype. Figures were produced using Servier Medical Art (http://www.servier.com/).

Figure 7

KLF Isoforms That Have Been Linked Either Directly or Indirectly With Complications That Are Associated With Diabetes Green indicates protective effect, and red indicates aggravating effect. The (+) sign indicates the Krüppel-like factor (KLF) isoforms that promote the phenotype described next to the organs. The (-) sign indicates alleviation of the phenotype. Figures were produced using Servier Medical Art (http://www.servier.com/).

Central Illustration

Krüppel-Like Factors Orchestrate Metabolic Pathways