Table 1.
Overview of IKKβ modulation and mechanism in cardiometabolic diseases.
| Cell Type | IKKβ modulation | Effect on cardiometabolic diseases | Mechanism | Reference |
|---|---|---|---|---|
| Endothelial Cells | Constitutive activation | Accelerated atherosclerotic development and progression, increased macrophage infiltration | 1. Upregulation of endothelial NF-κB mediated gene expression of cytokines/chemokines (CCL2, CCL12, IL-1β, IL-6, CXCR4), increased macrophage infiltration 2. Cellular transition of SMC to macrophage-like cells |
(29) |
| Myeloid Cells | Knockout | Increased lesion size, more severe lesion, increased necrosis, increase macrophage content at the lesion site | 1. Reduction of IL-10 anti-inflammatory cytokine | (33) |
| Myeloid Cells | Knockout | Decreased lesion size, macrophage infiltration, and foam cell formation | 1. Reduction in macrophage/lesional NF-κB-mediated proinflammatory gene expression/protein level (MCP-1, TNFα, IL-1β, IL-1α, VCAM-1, ICAM-1), reducing macrophage recruitment and infiltration 2. Reduced scavenger receptor expression levels, decreased ox-LDL uptake by macrophages |
(36) |
| VSMC | Knockout | Decreased lesion size | 1. Reduction in lesion proinflammatory protein level (MCP-1, TNFα, IL-1β) | (39) |
| Adipocytes | Knockout | Increased plaque vulnerability | 1. Upregulation of aortic/lesional NF-κB mediated gene expression of cytokines/chemokines/protein levels (MCP-1, TNFα, IL-1β, IL-6, VCAM-1, ICAM-1) | (41) |
| MSC | Gain of function | Promoted adipogenesis and inhibits osteogenesis | 1. Increases adipogenic genes (Zfp423, PPARγ) 2.Tags β-catenin for β-TrCP-mediated ubiquitination leading to adipogenesis | (55) |
| MSC, MEFs | Knockdown with various methods | Inhibited adipogenesis and promotes osteogenesis | 1. Suppresses adipogenic genes (Zfp423, PPARγ) 2. Reduced β-catenin ubiquitination leading to osteogenesis |
(55) |
| White adipose lineage | Knockout | Decreased obesity; improved glucose tolerance; protected from hepatic steatosis | 1. Suppresses adipogenic genes (Zfp423, PPARγ, C/EBPα) 2. Decreases Smurf2 levels resulting in increased β-catenin activity 3. Reduced macrophage infiltration in WAT 4. Decrease in hepatic lipogenic genes (SREBP1c, ScD-1, PPARγ) |
(39, 54) |
| Human stem cells | Pharmacological inhibition | Inhibited adipogenesis | 1. Suppresses adipogenic genes (Zfp423, PPARγ, C/EBPα) 2. Decreases Smurf2 levels resulting in increased β-catenin activity |
(54) |
| Adipocytes | Knockout | Increased adipocyte death; macrophage infiltration; defective adipose remodeling; impaired insulin signaling | 1. Increases pro-apoptotic genes (XIAP, Bcl2) 2. Activation of proapoptotic protein BAD 3. Increases adipose lipolysis 4. Increase in WAT proinflammatory genes (TNFα, MCP-1, IL-2) |
(59) |
| Hypothalamic AGRP neurons | Knockout | Anti-obese phenotype; reduced glucose intolerance; preserved insulin and leptin signaling | 1. Reduction of SOCS3 | (95) |
| Mediobasal Hypothalamus | Constitutive activation | Impaired central insulin and leptin signaling | 1. Decreased Akt and PIP3 activation 2. Increased SOCS3 |
(95) |
| Systemic | Pharmacological inhibition | Reduced high sucrose diet (HSD)-induced obesity; prevented hepatic steatosis and NASH |
1. Reduced WAT inflammation (TNFα, F4/80) 2. Reduced NF-κB-mediated liver inflammation 3. Upregulation of PPARα and PPARγ leading to increased β-oxidation (CPT-1 and ACOX) |
(92) |
| Adipocytes | Constitutive activation | Decreased lipid deposits into other tissue (i.e., hepatosteaotosis); improved systemic insulin resistance | 1. Increased energy expenditure through hypothesized mechanisms: increased thermogenesis and fatty acid oxidation (upregulation of CPT-1β, ACO1), increase in mitochondria biogenesis (upregulation of NRF1), elevated IL-6 levels 2. Decreased body weight and systemic inflammation |
(58) |
| Hepatocytes | Knockout | Improved hepatic insulin resistance, sustained peripheral insulin resistance | 1. Decrease in proinflammatory gene expression (IL-6) in liver | (77) |
| Myocytes | Knockout | Retained systemic insulin resistance | 1. Maintained high TNFα expression in WAT; low IR activation | (87) |
| Myeloid cells | Knockout | Improved systemic insulin resistance | 1. Decrease in proinflammatory gene expression (IL-6) | (77) |
| Hepatocytes | Constitutive activeation | Increased liver and peripheral insulin resistance | 1. Increased expression of circulating IL-6 | (51) |
| Hepatocytes | Overexpression | Improved insulin sensitivity; improved glucose homeostasis | 1. Increased XBP1 stability/decreased XBP1 degradation via IKKβ mediated phosphorylation | (78) |
| Astrocytes | Overexpression | Induced metabolic syndromes | 1. Decreased astrocyte plasticity leading to increased GABA and increased GABA inhibition of BDNF secreting neurons | (106) |
| Mediobasal Hypothalamus | Activation | Increased obesity and insulin resistance | 1. Loss of neuronal development | (108) |
| Hypothalamic AGRP neurons | Activation | Impaired glucose homeostasis; no change in body weight or leptin signaling | 1. Increased AGRP firing | (103) |
| Systemic | Pharmacological inhibition | Alleviated insulin resistance | 1. Reduction of ectopic IRS-1 serine phosphorylation 2. Restoration of IRS-1 phosphorylation and protein levels 3. Enhanced Akt activity 4. Increased glucose uptake 5. Increased glycolysis and glycogen/lipid synthesis |
(54, 68–74) |
| Adipocyte | Knockout | Worsened insulin resistance; enhanced inflammation | 1. Reduction of IL-13 | (60) |
| Hepatocytes | Constitutive activation | Increased liver fibrosis | 1. Increased inflammation (chemokines) and macrophage infiltration in the liver | (94) |