Table 2.
Upstream Regulator | Activation Z Score | P‐Value of Overlap | Function |
---|---|---|---|
Lipid metabolism | |||
PPARA* | 7.782 | 2.65E‐86 | Major regulator of lipid metabolism; also regulator of cell death and apoptosis |
PPARG | 7.287 | 7.19E‐11 | PPARG regulates fatty acid storage and glucose metabolism |
SREBF2 | 5.048 | 1.77E‐16 | Controls cholesterol homeostasis by stimulating transcription of sterol‐regulated genes |
SREBF1 | 4.822 | 4.53E‐18 | Involved in sterol biosynthesis |
Nr1h/LXR | 4.286 | 1.00E‐05 | Important regulator of cholesterol, fatty acid, and glucose homeostasis |
PPARGC1B | 3.996 | 1.50E‐06 | Involved in fat oxidation |
PPARD | 3.740 | 2.78E‐22 | Regulates the peroxisomal beta‐oxidation pathway of fatty acids |
ESRRA | 3.516 | 1.20E‐03 | Regulator of fatty acid metabolism |
FGF21 | 3.129 | 2.17E‐04 | Involved in lipid metabolism and ketogenesis |
Inflammatory response | |||
STAT1* | −7.130 | 1.63E‐13 | Important for cell viability in response to different cell stimuli and pathogens; key modulator of cell death |
IRF7 | −6.888 | 2.63E‐17 | Regulator of many interferon‐alpha genes |
Interferon alpha | −6.710 | 2.93E‐15 | Subgroup of interferon proteins involved primarily in innate immune response against viral infection |
IFNG* | −6.543 | 4.59E‐20 | Cytokine that induces an inflammatory response and apoptotic cell death |
TNF* | −5.733 | 5.83E‐18 | Proinflammatory cytokine secreted primarily by macrophages; inducer of cell death, apoptosis |
Ifnar | −5.682 | 3.98E‐17 | Receptor which binds endogenous type I interferon cytokines |
IRF3* | −5.555 | 2.01E‐14 | Mediates cellular antiviral responses by both inducing antiviral genes and triggering apoptosis |
NFkB (complex) | −4.873 | 2.39E‐06 | Key regulator of immune and inflammatory responses |
IRF1* | −4.791 | 9.55E‐12 | Regulator of immune response, apoptosis, and DNA damage |
TLR3 | −4.753 | 3.52E‐08 | A member of the toll‐like receptor family of pattern recognition receptors of the innate immune system |
TLR9* | −4.722 | 4.88E‐05 | Receptor expressed in, e.g., dendritic cells, macrophages, natural killer cells; may activate apoptosis |
TLR7* | −4.594 | 1.75E‐04 | Plays an important role in pathogen recognition and activation of innate immunity; may activate apoptosis |
IL21 | −4.589 | 2.66E‐04 | Cytokine with immunoregulatory activity; may promote the transition between innate and adaptive immunity |
CHUK* | −4.553 | 1.19E‐03 | Part of the IκB kinase complex; also plays a role in cell death and cell proliferation |
NFATC2 | −4.409 | 3.74E‐04 | Pays a central role in inducing gene transcription during the immune response |
IKBKB* | −4.344 | 6.79E‐04 | Protein subunit of IκB kinase; blocks NF‐κB activation; also plays a role in cell death and cell proliferation |
IRF5* | −4.340 | 9.58E‐05 | Acts as a molecular switch to control whether macrophages promote or inhibit inflammation; promotes cell death |
TLR4 | −4.329 | 7.39E‐06 | Activator of intracellular signaling pathway NF‐κB and inflammatory cytokine production |
RELA* | −4.272 | 9.23E‐07 | Involved in NFκB heterodimer formation, nuclear translocation, and activation; also proto‐oncogene |
IKBKG* | −4.136 | 2.06E‐04 | A subunit of the IκB kinase complex that activates NF‐κB; also plays a role in cell death and cell proliferation |
Ifn | −3.968 | 9.97E‐12 | Group of cytokines produced by host cells in response to the presence of several pathogens |
IFN alpha/beta | −3.715 | 2.64E‐07 | Cytokines involved primarily in innate immune response |
IFN type 1 | −3.701 | 3.05E‐07 | Large subgroup of interferon proteins that help regulate the activity of the immune system |
IL2 | −3.676 | 1.46E‐03 | Cytokine that stimulates the growth of T‐cell lymphocytes |
IL1 | −3.629 | 1.35E‐02 | Group of cytokines that plays a central role in the regulation of immune and inflammatory responses |
IL1A | −3.492 | 4.40E‐03 | A cytokine that plays one of the central roles in the regulation of the immune responses |
IL6* | −3.485 | 5.83E‐06 | A pro‐inflammatory cytokine; associated with necrosis |
JAK2* | −3.397 | 9.62E‐04 | Mediates essential signaling events in both innate and adaptive immunity; delays cell death |
C3* | −3.332 | 4.92E‐04 | A protein of the immune system; associated with liver damage |
IL1B* | −3.255 | 2.32E‐13 | An important mediator of the inflammatory response; also involved in cell proliferation, differentiation, and apoptosis |
CD14* | −3.244 | 1.78E‐02 | A component of the innate immune system; expressed on monocytes/macrophage; plays a role in apoptototic cell clearance |
CSF2 | −3.225 | 1.84E‐05 | Stimulates stem cells to produce granulocytes and monocytes |
IL6R* | −3.219 | 2.64E‐03 | IL‐6 receptor; plays an important role in immune response |
IL12 (complex) | −3.174 | 8.76E‐04 | A T cell–stimulating factor |
C5 | −3.062 | 4.58E‐03 | Plays an important role in inflammatory and cell killing processes |
CSF1 | −3.048 | 1.70E‐06 | Cytokine that influences differentiation into macrophages or other related cell types |
OSM* | −3.023 | 1.24E‐07 | A pleiotropic cytokine that belongs to the IL‐6 group of cytokines; inducer of cell death |
IL10RA | 3.366 | 3.46E‐14 | IL‐10 receptor; inhibits the synthesis of proinflammatory cytokines |
IL1RN* | 3.834 | 7.40E‐08 | IL‐1 inhibitor |
Energy production | |||
INSR | 6.234 | 4.75E‐10 | Insulin receptor that plays a key role in the regulation of glucose homeostasis |
PPARGC1A | 4.090 | 1.42E‐14 | Regulator of mitochondrial biogenesis and function |
PPARGC1B | 3.996 | 1.50E‐06 | Involved in nonoxidative glucose metabolism and energy expenditure |
ESRRA | 3.516 | 1.20E‐03 | Regulator of mitochondrial biogenesis, gluconeogenesis, and oxidative phosphorylation |
Effect of icosabutate on hepatic gene expression involved in lipid metabolism, inflammatory response, and energy production. High fat/cholesterol–fed APOE*3Leiden.CETP mice were left untreated or treated with icosabutate for 20 weeks. Data represent the predicted activation state (z score ≤ 3 or > 3) of the upstream regulators, based on the expression changes of known target genes. The overlap p value indicates the significance of the overlap between the known target genes of a transcription factor and the differentially expressed genes measured in an experiment. Red color indicates up‐regulation; green color indicates down‐regulation.
Indicates upstream regulators that are involved in liver necrosis, cell death, or apoptosis as well.
Abbreviations: C, complement; CD14, cluster of differentiation 14; CHUK, component of inhibitor of NFκB; CSF, colony stimulating factor; ESRA, estrogen receptor alpha; ESRRA, estrogen related receptor alpha; FGF21, fibroblast growth factor 21; IFN, interferon; Ifnar, interferon‐α/β receptor; IFNG, interferon gamma; IKBKB, inhibitor of NFκB subunit beta; IKBKG, inhibitor of NFκB subunit gamma; IL1RA, interleukin 1 receptor antagonist; IL10RA, interleukin 10 receptor subunit alpha; INSR, insulin receptor; IRF, interferon regulatory factor; JAK2, janus kinase 2; LXR, liver X receptor; NFATC2, nuclear factor of activated T‐cells, cytoplasmic 2; NFκB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; Nr1h: nuclear receptor family; OSM, oncostatin M; PPARA, PPAR‐alpha; PPARD, PPAR‐delta; PPARGC1B, PPARG Coactivator 1 Beta; RELA, REL‐associated protein involved in NFκB heterodimer formation; SREBF, sterol regulatory element binding transcription factor; TLR, toll‐like receptor; TNF, tumor necrosis factor.