THE JOURNAL OF BIOLOGICAL CHEMISTRY
Minireview
Roles of CCAAT/Enhancer-
binding Proteins in Regulation
of Liver Regenerative Growth*
Anna Mae Diehl‡
From The Johns Hopkins University,
Baltimore, Maryland 21205
The expressions and activities of several CCAAT/en-
hancer-binding proteins (C/EBP) isoforms fluctuate in
the regenerating liver. The physiological implications of
these variations in C/EBP function remain poorly char-
acterized in the setting of regeneration. However, les-
sons learned in various hepatocyte cell lines and by
studying primary hepatocytes from transgenic C/EBPa-
deficient mice suggest that the C/EBP isoforms are
likely to influence proliferation, differentiated gene ex-
pression, and survival in mature, adult hepatocytes. In
addition, these factors are potentially important modu-
lators of liver nonparenchymal cell genes, including
those that encode matrix molecules and growth factors
that are required for successful liver regeneration. The
possibility that members of the C/EBP family of tran-
scription factors actively participate in many aspects of
the regenerative response to liver injury is strength-
ened by growing evidence that many hepatocyte mito-
gens and co-mitogens regulate C/EBP activity. Further-
more, the C/EBPs themselves appear to regulate the
expression of some of these growth regulators.
Liver regeneration is a complex physiological response to
liver injury during which the surviving, mature hepatocytes
and liver nonparenchymal cells proliferate to reconstitute the
pre-morbid mass of the damaged organ. The liver is one of the
few tissues in adult vertebrates that retains the capacity for
regeneration. However, such compensatory hyperplasia re-
quires careful orchestration to assure that vital liver-specific
functions are preserved while hepatocytes, which generally do
not proliferate in adult animals, replicate. The study of organ-
isms that are as divergent as urodeles and humans has iden-
tified common, fundamental processes that are required for the
regeneration of any tissue. This work indicates that regenera-
tion occurs only if injury-related changes in the local extracel-
lular environment motivate differentiated, but proliferation-
competent, cells to reenter the cell cycle while the normal
homeostatic mechanisms that couple cell cycle reentry to cell
death are suspended (1–3). Although much has been learned
about the mechanisms that regulate hepatic regeneration,
many aspects of the process remain poorly understood.
* This minireview will be reprinted in the 1998 Minireview Compen-
dium, which will be available in December, 1998. This is the fourth
article of five in the “Biological Role of the Isoforms of C/EBP Minire-
view Series.”
‡ To whom correspondence should be addressed: 912 Ross Bldg., The
Johns Hopkins University, 720 Rutland St., Baltimore, MD 21205. Tel.:
410-955-7316; Fax: 410-955-9677; E-mail: amdiehl@welchlink.
welch.jhu.edu.
This paper is available on line at http://www.jbc.org
Vol. 273, No. 46, Issue of November 20, pp. 30843–30846, 1998
© 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
CCAAT/Enhancer-binding Proteins and
Hepatocyte Proliferation
CCAAT/enhancer-binding proteins (C/EBPs)1 are known to
play important roles in regulating the expression of multiple
hepatocyte-specific genes (4). These transcription factors also
help to control hepatocyte progression through the cell cycle (5,
6). Thus, the C/EBPs are likely to be important targets for
regulation during liver regeneration. Consistent with this con-
cept, variations in the expression of C/EBP mRNAs, proteins,
and DNA binding activities have been documented during liver
regeneration. C/EBPa is the predominant C/EBP isoform that
is expressed by adult hepatocytes in healthy livers. During the
initial 24 h after 70% (partial) hepatectomy (PH), levels of
C/EBPa mRNA and protein decline transiently. This is associ-
ated with decreased binding activity of C/EBPa homodimers in
gel mobility shift assays. Decreases in C/EBPa are preceded by
the induction of other C/EBP isoforms. The level of C/EBPb and
C/EBPd mRNAs, proteins, and DNA binding activities in-
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creases in the early pre-replicative period following PH and
returns to base line as hepatocytes enter S phase (7–10).
The importance of these reciprocal variations in C/EBPa and
other C/EBP isoforms in regulating hepatocyte proliferation
during liver regeneration has been debated. Present contro-
versy stems from an apparently poor correlation between the
induction of C/EBPb DNA binding activity and hepatocyte pro-
liferation in transgenic mice strains with disruption of certain
cytokines or cytokine receptors. Mice homozygous for a deletion
in the gene for the type 1 TNF receptor have extremely limited
hepatocyte proliferation after PH and yet exhibit apparently
normal induction of total C/EBP DNA binding activity during
the early pre-replicative period (11). In contrast, transgenic
mice lacking the gene for type 2 TNF receptors demonstrate
normal hepatocyte proliferation after PH but decreased induc-
tion of C/EBPb DNA binding activity (12). Furthermore, liver
regeneration is severely inhibited in IL-6-null mice, although
these animals exhibit normal induction of C/EBPb mRNAs
after PH (13). However, because C/EBP function is regulated,
to a large extent, by post-transcriptional modifications of the
C/EBPs themselves, as well as by their interactions with spe-
cific dimerization partners (14 –21), the former observations do
not preclude an important role for the C/EBPs as regulators of
hepatocyte proliferation during liver regeneration. Indeed,
other evidence supports the biological importance of the
C/EBPs as physiologically relevant regulators of hepatocyte
proliferation. Transgenic mice with a deleted C/EBPa gene
have increased hepatocyte proliferation at birth (22, 23). Be-
cause these animals do not survive long enough to permit
evaluation of their response to PH, whether or not C/EBPa
deletion enhances hepatocyte proliferation during liver regen-
eration has not been tested. However, hepatocytes isolated
from these mice do have increased proliferative activity in
culture (24). Conversely, enforced overexpression of C/EBPa
has been shown to inhibit proliferation in several different
hepatocyte cell lines (5, 25, 26). Thus, it seems reasonable to
conclude that changes in the relative amounts (or activities) of
C/EBPa and other C/EBP isoforms influence the proliferative
1
The abbreviations used are: C/EBP, CCAAT/enhancer-binding pro-
tein; PH, 70% (partial) hepatectomy; TNF, tumor necrosis factor; IL,
interleukin; iNOS, inducible nitric oxide synthase; NO, nitric oxide;
HGF, hepatocyte growth factor.
30843
30844 Minireview: Regulation of Liver Regenerative Growth
activity of hepatocytes during liver regeneration. However, be-
cause of the complexity of the C/EBP family of transcription
factors, the multiple extracellular signals that regulate C/EBP
activities, and the fact that hepatocytes co-express several dif-
ferent C/EBP isoforms, the role of each C/EBP family member
in the regulation of hepatocyte proliferation during liver regen-
eration remains uncertain. Now that transgenic mice have
been developed with targeted disruption of different C/EBP
genes, it will be possible to use these mice to delineate the
relative importance of different C/EBP isoforms as regulators
of the hepatocyte proliferative response in vivo. Indeed, Green-
baum and colleagues have reported preliminary evidence that
C/EBPb knock-out mice exhibit impaired hepatocyte prolifera-
tion and decreased liver regeneration after PH.2
There are several mechanisms by which the C/EBPs may
regulate hepatocyte proliferation. C/EBPa is known to stabilize
p21/WAF, a protein that inhibits transition from the pre-rep-
licative (G1) period into S phase (5). Because induction of
C/EBPb and C/EBPd during the early pre-replicative period
may inhibit subsequent C/EBPa activity by repressing C/EBPa
gene expression, reciprocal variations in C/EBP isoforms could
release hepatocytes from C/EBPa-mediated cell cycle arrest.
There is also some evidence that C/EBPb may positively regu-
late the expression of genes that promote cell cycle progression.
For example, C/EBP consensus sequences have been identified
in the regulatory regions of cyclin D2 (27) and cyclin A (28) and
may also interact with the retinoblastoma protein (RB) (29).
In addition to promoting hepatocyte proliferation, changes in
the relative expression of different C/EBP isoforms may affect
global changes in hepatocyte gene expression that permit these
cells to survive the “stress” of regeneration. For example,
C/EBPb and -d are important in modulating the expression of
various acute phase response genes, including those such as
inducible nitric oxide synthase (iNOS) (30 –32), that are
thought to protect hepatocytes from cytokine-mediated toxicity
(33–37). The activity of iNOS and production of nitric oxide
(NO) increase in hepatocytes in the mid-late pre-replicative
period following PH (38 – 40). NO has diverse biological actions
and has recently been shown to inhibit caspase 3 activation by
TNFa (33, 41). Given the pivotal role that caspase 3 plays in
apoptosis (42– 44), C/EBPb-mediated induction of NO produc-
tion may be one of the mechanisms that prevents injury-related
cytokines from causing hepatocyte apoptosis in the regenerat-
ing liver. Preliminary experiments in iNOS-deficient trans-
genic mice support this view.3
Although liver regeneration imposes a tremendous drain on
hepatocyte ATP stores, hepatocyte necrosis is not normally
increased by PH. Changes in the expression of phosphoenol-
pyruvate carboxykinase, glycogen synthase, and many other
genes that regulate hepatic metabolism occur quickly after PH
(45– 47). C/EBPb and -d are important transcriptional regula-
tors of many of the genes that are involved in metabolism
(48 –50). As such, these transcription factors modify hepatocyte
substrate utilization to assure energy homeostasis during the
period of intense proliferative activity. Because failure to meet
the increased ATP requirements during regenerative growth
could lead to hepatocyte ATP depletion and necrosis, successful
regulation of C/EBP activity may be important for thwarting
hepatocyte necrosis during the regenerative response to injury.
C/EBPs and Liver Nonparenchymal Cells
Successful regeneration of the liver requires much more than
the proliferation of hepatocytes. Cells that form supporting
structures, such as bile ducts and blood vessels, must also
2 4
L. Greenbaum, FASEB Conference, Snomass, CO, July, 1998.
3
A. M. Diehl and R. Rai, unpublished data.
replicate. In addition, new matrix must be deposited to provide
a scaffolding for the “rebuilding” effort. Furthermore, evidence
that hepatocyte proliferation is driven largely by factors that
are produced within the regenerating liver implies that de novo
synthesis of autocrine and paracrine growth regulatory factors
must follow liver injury (2). The importance of the C/EBPs in
regulating these aspects of the hepatic regenerative response
has barely been evaluated.
Matrix Production
Workers in the field of hepatic fibrogenesis have long recog-
nized that inflammation initiates fibrosis. The molecular basis
for this observation is being discovered. Injury-related cyto-
kines, such as TNFa and IL-6, and oxidant stress are known to
induce several transcription factors, including C/EBPb, that
activate transcription of the type I collagen gene in stellate
cells (2). C/EBP sites have also been identified in the promoters
of metalloproteinases (51). Thus, the C/EBPs are likely to reg-
ulate matrix production and remodeling by hepatic nonparen-
chymal cells during liver regeneration.
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Production of Paracrine and Autocrine Growth Regulators
Hepatocyte Growth Factor (HGF)—Stellate cells are also the
principal source of the hepatocyte mitogen, HGF, in the regen-
erating liver (2). The regulatory regions of the HGF gene con-
tain C/EBP consensus motifs (52), and recently, C/EBPb was
shown to trans-activate HGF gene expression. Furthermore,
recombinant TNFa induces a dose-dependent increase in IL-6
expression in primary stellate cell cultures. This is followed by
increased C/EBPb DNA binding activity and induction of HGF
mRNA expression.4 These observations suggest that the
C/EBPs play a role in regulating the production of paracrine
growth factors in the regenerating liver. Definitive proof of this
concept awaits analysis of HGF gene induction in the liver
remnants of C/EBPb knock-out mice that have been subjected
to PH.
TNFa and TNF-regulated Cytokines—Injury-related cyto-
kines, particularly TNFa and IL-6, are now widely acknowl-
edged to play pivotal parts in the initiation of hepatocyte pro-
liferation after PH (11, 13, 54, 55), although the relative
importance and precise roles of these factors during liver re-
generation remain a topic of considerable debate. Binding sites
for C/EBPb have been identified in the promoters of a large
number of cytokine genes, including TNFa, IL-1, -6, and -8, and
granulocyte colony-stimulating factor (56 –59). Transfection
studies with TNFa reporter gene constructs have demon-
strated that C/EBPb is much more active than C/EBPa as an
inducer of TNF gene transcription. Furthermore, C/EBPb and
-d are the predominate C/EBP isoforms in activated macro-
phages, which produce large amounts of TNF and TNF-induc-
ible cytokines. Consistent with the concept that C/EBPb is
important for TNF induction, inflammation-related increases
in serum TNFa concentrations are blunted in C/EBPb-deficient
transgenic mice. This observation suggests that decreased pro-
duction of TNFa may contribute to the impaired liver regener-
ation that Greenbaum’s group has noted in C/EBPb knock-out
mice. Decreases in TNFa, in turn, would be expected to influ-
ence the relative abundance of C/EBP family members in the
nuclei of hepatocytes and other TNF target cells because TNF
or peptide ligands that specifically activate type 1 or type 2
TNF receptors induce an almost instantaneous redistribution
of preformed C/EBPb and C/EBPd from the cytosol into the
nucleus (18). Although C/EBPb was initially proposed as a
R. Rai, F. Anania, S. Q. Yang, H. Z. Lin, J. J. Potter, and A. M. Diehl,
submitted for publication.
 Minireview: Regulation of Liver Regenerative Growth
FIG. 1. After PH, there is transient
inhibition of C/EBPa activity and in-
duction of C/EBPb and -d activities.
These reciprocal variations in C/EBP
family members modulate gene expres-
sion in different liver cell populations.
Some of the phenotypic consequences in
hepatocytes and liver nonparenchymal
cells (e.g. macrophages, endothelial cells,
stellate cells, and cholangiocytes) are
indicated.
potential mediator of the TNF-dependent induction of IL-6,
which occurs after PH (11, 54), studies using mice homozygous
for a deletion in the gene for C/EBPb demonstrate that C/EBPb
is not essential for IL-6 induction because these mice actually
develop increased circulating levels of IL-6 as they age (60).
Given this, it is unlikely that decreased induction of IL-6 con-
tributes to the impaired liver regeneration that Greenbaum’s
group has noted in the C/EBPb knock-out mice. Rather, these
observations demonstrate that organisms have developed
many mechanisms to preserve cytokine induction when any
given cytokine-induced transcription factor becomes deficient.
The latter may help to explain why IL-6 induction is not en-
tirely abolished in transgenic TNF receptor type 1-null mice
(11) or in rats that were pretreated with anti-TNF antibodies
before PH (54). Similarly, because IL-6 induces C/EBPb and
C/EBPb regulates the transcription of multiple cytokines, in-
cluding TNFa, it is difficult to assure that IL-6 is the only
cytokine that is deficient in transgenic mice in which the IL-6
gene has been disrupted experimentally.
Regulation of C/EBP Activity during
Liver Regeneration
C/EBP function is regulated at many levels, consistent with
the growing body of evidence which suggests that these factors
regulate critical events that are involved in cellular prolifera-
tion, differentiation, and survival. Several hormones (e.g. insu-
lin, glucagon, epinephrine, norepinephrine, and corticoste-
roids) that increase in the blood after PH (2) are known to
regulate either the expression or activity of various C/EBP
isoforms. For example, insulin has been shown to alter the
turnover of the 40 – 42 kDa C/EBPa proteins, accelerating their
30845
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degradation (61). Cyclic AMP is known to increase transcrip-
tion of C/EBPb and -d (61– 63). Hence, glucagon and epineph-
rine, which increase adenylyl cyclase activity and promote the
accumulation of hepatic cAMP in the early pre-replicative pe-
riod, are likely to play a role in the induction of these C/EBP
isoforms after PH. The cAMP-dependent kinase, protein kinase
A, has also been shown to influence the function of C/EBPb
protein by phosphorylating Ser299 (21). Norepinephrine and
other a-adrenergic agents that promote increases in intracel-
lular calcium and activate calmodulin-sensitive kinases in the
regenerating liver may also regulate C/EBPb because there is
evidence that Cam kinase II phosphorylation of C/EBPb alters
its DNA binding activity (20). Regenerative increases in circu-
lating corticosteroids may contribute to increase the expression
of C/EBPd mRNAs that have been observed in the regenerating
liver (63).
Several hepatocyte mitogens that regulate the hepatocyte
proliferative response during regeneration (including epider-
mal growth factor, transforming growth factor a, and HGF)
may also influence C/EBP function. These growth factors acti-
vate receptor tyrosine kinases that couple to mitogen-activated
kinases (64), which are known to phosphorylate C/EBPb (65).
Injury-related cytokines are also likely to play important roles
in regulating C/EBP function in the regenerating liver. For
example, IL-6 and IL-1b are well established inducers of
C/EBPb and C/EBPd mRNA expression, respectively (53),
whereas TNFa has been shown to increase the DNA binding
activity of C/EBPb and C/EBPd by affecting the nuclear local-
ization of these proteins (18). The latter appears to have phys-
iological relevance for liver regeneration because pretreatment
30846 Minireview: Regulation of Liver Regenerative Growth
with anti-TNF antibodies inhibits the nuclear accumulation of
these C/EBP isoforms and decreases their participation in DNA
complex formation after PH (46).
Thus, many factors that regulate the proliferation and dif-
ferentiated functions of hepatocytes during the regenerative
response are also known to effect the biological activity of the
C/EBPs. Given this and the fact that the C/EBPs regulate the
proliferation and differentiation of many types of cells, these
transcription factors are likely to be important downstream
targets for growth factor-initiated signals that drive the regen-
eration of the liver after it has been injured (Fig. 1). Definitive
proof of this concept as well as progress in delineating the
relative importance of various C/EBP family members during
liver regeneration is now possible by studying the regenerative
response to PH in transgenic mice strains with targeted dele-
tion(s) of specific C/EBP genes.
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 Roles of CCAAT/Enhancer-binding Proteins in Regulation of Liver Regenerative
Growth
Anna Mae Diehl
J. Biol. Chem. 1998, 273:30843-30846.
doi: 10.1074/jbc.273.47.30843

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