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Magee et al. Egr1 in liver metabolism and cancer

hormones. However, high intracellular cholesterol S transition, contributing to the final termination of
is toxic to cells and high blood levels of cholesterol regeneration [55] . Perturbations in the liver-regenerative
increase the risk for atherosclerosis development [44] . response cause prolonged liver injury and delayed
Therefore, the overall cholesterol level is tightly liver recovery.
controlled in the body. The liver plays a central role in
this regulation by balancing multiple pathways involved The role of Egr1 in liver regeneration was first
in de novo cholesterol biosynthesis, cholesterol suggested by animal studies demonstrating that Egr1
conversion to bile acids, biliary cholesterol excretion, was immediately induced during the initiation phase
and reverse cholesterol transport [45] . Sterol response of liver regeneration [56,57] . Using a transgenic Egr1
element binding proteins (SREBPs) are important luciferase (Egr1-luc) mouse model, Dussmann et al. [14]
transcription factors that regulate expression of genes demonstrated that Egr1 expression was increased
in lipid metabolism including fatty acids and cholesterol at the site of wound healing in partial hepatectomy.
synthesis. Three isoforms (SREBP-1a, SREBP-1c, Another earlier study showed that Egr1 expression
and SREBP-2) have been identified in mammals. significantly increased after 15 min and subsided within
SREBP-1 mainly regulates genes required for fatty 60 min after partial hepatectomy in rat livers [56] . More
acid biosynthesis and SREBP-2 is responsible for the recent studies in mice have extended the peak of Egr1
induction of genes involved in cholesterol biosynthesis induction to 12 h in partial hepatectomy-induced liver
and uptake, including HMG-CoA synthase (Hmgcs) regeneration [58] and to 2 h in carbon tetrachloride (CCl 4 )
and low-density lipoprotein receptor (Ldlr) [46] . exposure-induced liver regeneration [18] . The specific
signals that regulate Egr1 expression during liver
Egr1 regulates the expression of cholesterol regeneration are not quite understood, a number of
biosynthetic genes, such as Hmgcs, farnesyl- candidates are worthy of consideration. For example,
diphosphate synthase (Fdps), farnesyl-diphosphate extracellular ATP has been implicated as a potent
farnesyltransferase 1 (Fdft1), lanosterol synthase (Lss), stimulus for Egr1 expression [59] . P2Y purinoceptor
sterol-4α-carboxylate 3-dehydrogenase (Nsdhl), and 2 (P2Y2) is a G protein coupled receptor that is
malic enzyme (Me1), in rat hepatomaH4IIE cells [24] . activated by ATP in hepatocytes. The fact that the
Additionally, Egr1 acts in concert with SREBP-2 to induction of Egr1 is impaired in P2Y2 liver subjected
-/-
mediate insulin-induced cholesterol biosynthesis in the to partial hepatectomy indicates that P2Y2 may
[24]
liver . Oncostatin M (OM) is a gp130 family member regulate Egr1 expression during liver regeneration [60] .
produced by the F4/80-positive macrophages [47] . In Additional candidates that regulate Egr1 expression
human hepatoblastoma HepG2 cells, Egr1 is induced are likely to include interleukin-6 (IL-6) and C/EBPβ,
by OM and binds to the sterol-independent regulatory because the induction of Egr1 has been shown to be
element (SIRE) in LDLR promoter region with co- impaired in IL-6 or C/EBPβ liver subjected to partial
-/-
-/-
activator CCAAT/enhancer binding protein-beta (C/ hepatectomy [61,62] .
EBPβ) and activates LDLR transcription [48,49] . Together,
these studies point to Egr1 as an important modulator EGR1 is essential for cell-cycle entry and progression
of cholesterol metabolism in the liver. during liver regeneration as Egr1 directly regulates cell
cycle mediators. Lai et al. [63] found that Egr1-deficient
EGR1 AND LIVER REGENERATION mouse livers had a substantially lower recovery rate
after liver injury, which was accompanied with the
The liver has a tremendous capacity to regenerate reduced expression of cell cycle mediators such as
after injury, which is a highly coordinated process Cyclin D1, Cyclin E, and proliferating cell nuclear
involving both liver parenchymal and non-parenchymal antigen. After subcutaneous administration of CCl 4 ,
cells. During liver regeneration, adult hepatocytes enter Egr1-deficient mice exhibited increased liver injury
the cell cycle (G0 to G1) and progress through the cell and delayed cell cycle progression [18,58] . Acute ethanol
-/-
cycle (G1 to M) until liver mass is restored [50] . Many dosing of Egr1 mice also resulted in exacerbated
signals regulate the process of liver regeneration [51] . liver injury associated with impaired liver repair [64] .
For example, lipopolysaccharide and cytokines are Collectively, these studies suggest that Egr1 and its
important mediators of the initiation phase [52] . Growth regulated cell-cycle entry and progression is critical
factors such as hepatocyte growth factor (HGF) for liver regeneration. Additionally, Egr1 contributes to
and epidermal growth factor (EGF) regulate the the regulation of a large number of genes required for
progression phase [53] . TGF-β1 signals later terminate the regenerative response, including cell division cycle
hepatocyte proliferation [54] . Additionally, growth 20 (cdc20), a key regulator of the mitotic anaphase-
arrest-specific 1 (Gas1), a cell proliferation inhibitor, promoting complex, and cytokines necrosis factor-
is induced during liver regeneration at the cycle G1/ alpha (TNFα), IL-6, and lymphotoxin-beta [14,18,57,65,66] .

Hepatoma Research ¦ Volume 3 ¦ November 20, 2017 271