Skip to main content
. 2019 Dec 24;4(2):193–207. doi: 10.1002/hep4.1453

Table 2.

Upstream Regulators

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.