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Magee et al. Egr1 in liver metabolism and cancer

lipogenesis (de novo lipogenesis), which may account mRNA is highly increased in adipocytes from diabetic
for up to 30% of TAGs in steatotic livers [27] , or derive mice [35] . PI3K/Akt pathway is activated upon insulin
from the active uptake of circulating fatty acids into the stimulation, which is required for glucose uptake and
hepatocytes. glycogenesis to lower circulating glucose level [36] .
Meanwhile, insulin stimulates the activation of MAPK
Glucose and insulin regulate Egr1 expression (ERK1 and 2) that promotes insulin resistance [37] . Thus,
The contributions of glucose and insulin to Egr1 the balance between PI3K/Akt and MAPK signaling
expression have been extensively studied in a variety pathway is critical to maintain insulin sensitivity.
of tissues and cell types. One earlier study showed that Egr1 transcriptionally regulates phosphatase and
glucose rapidly and transiently induces Egr1 mRNA tensin homologue (PTEN), a suppressor of PI3K/Akt
in SV40-transformed murine pancreatic beta-cell line signaling [38] . Meanwhile, Egr1 regulates geranylgeranyl
MIN6 cells that is accompanied with an induction pyrophosphate synthase (GGPPS), an activator of
of insulin [28] . This study also demonstrated that the ERK/MAPK signaling [39] . Thus, inhibiting Egr1 in
induction of Egr1 by glucose was unique to beta cells adipocyte simultaneously blocks MAPK signaling
since glucose couldn’t induce Egr1 expression in NIH- and augments PI3K/Akt signaling, and subsequently
3T3 fibroblasts or hepatocytes [28] . The results raise a improves insulin sensitivity [40] . Collectively, these
question whether glucose regulates Egr1 expression studies suggest that pharmacological targeting
requires insulin signaling activation. Later, another adipocyte Egr1 could be potentially applied for
study showed that in vascular endothelial cells, developing novel treatment for T2DM.
glucose and insulin independently regulated Egr1
expression and they had an additive effect to induce Obesity commonly coexists with Insulin resistance.
Egr1 in the co-treatment [29] . Specifically, glucose The link of Egr1 to obesity and obesity-associated
mediates its effects through activation of PKC while fatty liver has been reported in mouse studies. For
insulin acts through the extracellular signal-regulated example, whole body Egr1-deficient mice fed a high
kinase (ERK1/2) pathway [29] . Collectively, these studies fat diet are less susceptible to diet-induced obesity
suggest that glucose or insulin differentially regulates and obesity-associated disorders such as insulin
Egr1 expression in a cell-type dependent manner. resistance, hyperinsulinemia, hyperlipidemia, and fatty
liver, which largely depends on the increase of energy
Insulin regulates Egr1 expression in hepatoma cells [9] expenditure in the adipose tissue of Egr1-null mice [20] .
and in non-liver-derived cells overexpressed with These studies suggest that the upregulation of Egr1
[9]
insulin receptors [30,31] . Keeton et al. showed that in in adipocytes is involved in promoting metabolic
rat hepatoma H4IIE cells, insulin treatment rapidly and disorders and that targeting Egr1 in adipocyte could
transiently induced Egr1 mRNA, reaching its maximum be useful for the obesity treatment.
levels by 15 min, which was coordinately regulated by
a regulatory network involving MAPK kinase (MEK)- The report of Egr1 function in liver steatosis is
ERK, p38 MAPK, and PI3-kinase (PI3K). In addition, somehow contradictory. One earlier study showed
the authors found that the activation of ERK1/2 was that Egr1 expression levels in the liver are positively
essential for the induction of Egr1 in response to correlated to high caloric intake in mice, humans,
insulin that could be further modulated by alterations and non-human primates [41] . In addition, whole-
[9]
-/-
in the activity of the p38 MAPK pathway . By body Egr1 mice are protected from chronic ethanol-
contrast, inhibition of the PI3K pathway augmented induced fatty liver due to the decreased expression
insulin’s effect on Egr1 expression, suggesting that and release of TNFα from macrophages [42] . However,
some factor downstream of PI3K may partially inhibit recent studies highlight that increasing Egr1 levels in
induction of Egr1. Of particular interests, Egr1 has been the liver ameliorates diet-induced fatty liver disease.
implicated to mediate the regulation of insulin on genes For example, the white pitaya (hylocereusundatus)
in liver metabolism, including hepatic malic enzyme juice attenuates diet-induced liver steatosis and
(ME) [32,33] and apolipoprotein A-I gene (ApoA1) [34] . improves insulin sensitivity in C57BL/6J mice, which
Taken together, these studies suggest that induction of is accompanied by an increase in hepatic Egr1 mRNA
Egr1 in response to insulin is vital to insulin’s action on level [43] . Thus, future research focusing on hepatocyte-
liver metabolism. specific Egr1 function in liver metabolism will be very
valuable.
Egr1, insulin resistance, and obesity
Insulin resistance is a central defect in type 2 diabetes Egr1 and cholesterol biosynthesis
mellitus (T2DM). The link between Egr1 and insulin Cholesterol is an essential component for cell
resistance is originally from the observation that Egr1 membrane and serves as the precursor to all steroid

270 Hepatoma Research ¦ Volume 3 ¦ November 20, 2017