Review Article

Curcumin and Liver Disease Laura Vera-Ramirez1,2

rez-Lopez3
Patricia Pe
Alfonso Varela-Lopez3
MCarmen Ramirez-Tortosa4
Maurizio Battino5
1
GENyO Center Pfizer-University of Granada & Andalusian Government Jose
L. Quiles3*
Centre for Genomics & Oncology, Granada, Spain
2
Department of Oncology, Complejo Hospitalario de Jaen, Jaen, Spain
3

Mataix Verdu
Institute of Nutrition and Food Technology ‘‘Jose
’’,
Department of Physiology, University of Granada, Granada, Spain
4

Mataix Verdu
Institute of Nutrition and Food Technology ‘‘Jose
’’,
Department of Biochemistry and Molecular Biology II,
University of Granada, Granada, Spain
5
Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche,
Facolta di Medicina, Universita Politecnica delle Marche, Ancona, Italy

Abstract
Liver diseases pose a major medical problem worldwide and
a wide variety of herbs have been studied for the manage-
ment of liver-related diseases. In this respect, curcumin has
long been used in traditional medicine, and in recent years it
has been the object of increasing research interest. In com-
bating liver diseases, it seems clear that curcumin exerts a
hypolipidic effect, which prevents the fatty acid accumulation
in the hepatocytes that may result from metabolic imbalan-
ces, and which may cause nonalcoholic steatohepatitis.
Another crucial protective activity of curcumin, not only in
the context of chronic liver diseases but also regarding
carcinogenesis and other age-related processes, is its potent
antioxidant activity, which affects multiple processes and
signaling pathways. The effects of curcumin on NF-jb are
crucial to our understanding of the potent hepatoprotective
role of this herb-derived micronutrient. Because curcumin is
a micronutrient that is closely related to cellular redox
balance, its properties and activity give rise to a series of
molecular reactions that in every case and biological
situation affect the mitochondria. C
V 2013 BioFactors,
39(1):88–100, 2013

Keywords: curcuma; cirrhosis; cytokines; fibrosis; hepatology;

inflammation; mitochondria; nuclear factors; oxidative stress;
steatohepatitis; steatosis

1. Introduction
Liver diseases represent a major medical problem all over the
world. In Europe and North America, alcohol abuse and overnu-
trition are the major causes of pathological conditions of the
liver (with viral hepatitis increasing), whereas in Africa and
C 2013 International Union of Biochemistry and Molecular Biology, Inc.
V
Volume 39, Number 1, January/February 2013, Pages 88–100
*Address for correspondence to: Jose
L. Quiles, Ph.D., Instituto de

n y Tecnologı́a de los Alimentos ‘‘Jose
Nutricio
Mataix Verdu
’’, Universidad
de Granada, Centro de Investigacio
n Biome
dica, Parque Tecnolo
gico de
Ciencias de la Salud, Lab. 120, Avenida del Conocimiento s/n, 18071
Granada, Spain. Tel.:þ34 958241000, Ext. 20316; Fax:þ34 958241000 Ext.
20316; E-mail: jlquiles@ugr.es.
Received 30 July 2012; accepted 13 September 2012
DOI: 10.1002/biof.1057
Published online 10 January 2013 in Wiley Online Library
(wileyonlinelibrary.com)
Asia, the main concerns are viral and parasitic infections. More-
over, unlike other major causes of mortality, liver disease rates
are increasing rather than declining [1]. The liver is the largest
internal organ and it performs a great number of functions, sup-
ported by its different cell types [2,3]. Hepatocytes, present at
the hepatic parenchyma, represent around 70% of the liver cell
population. Hepatocytes are implicated in the secretion of pro-
teins and bile, in cholesterol metabolism, and in the metabolism
of glucose and glycogen. Detoxification, the metabolism of urea,
acute phase response, and blood clotting are other functions
performed by hepatocytes. Cholangiocyte or bile duct cells are
present in the duct epithelium and represent around 3% of the
liver cell population. They transport bile, control the rate of bile
flow, and secrete water and bicarbonate to control the pH of
bile. Endothelial cells are present at the liver vasculature, con-
trolling blood flow and contributing to parenchymal zonation.
Liver sinusoidal endothelial cells constitute around 2.5% of the
lobular parenchyma and form the sinusoidal plexus to facilitate

88 BioFactors
 Main liver diseases
TABLE 1

Neoplastic liver Hepatocellular carcinoma

diseases
Hepatoblastoma
Cholangiocarcinoma
Primary hepatic angiosarcoma
Non-neoplastic Alcohol-related disease
liver diseases
Hepatic cholestasis
Nonalcoholic fatty liver diseases (NAFLD)
Nonalcoholic steatohepatitis (NASH)
Human hepatitis viruses

The liver lobule. Hepatic toxicity

FIG 1
blood circulation. They also enable the transfer of molecules
and proteins between serum and hepatocytes, and are active in
the scavenging of macromolecular waste, in cytokine secretion,
antigen presentation, and blood clotting. Hepatic stellate cells
(HSCs) are situated in a perisinusoidal position and represent
around 1.4% of liver cells. Their functions are the maintenance of
the extracellular matrix, vitamin A storage, control of vascular
tone, contribution of regenerative response to injury, the
secretion of cytokines, and to act as precursors of myofibroblasts.
The activation of HSCs is the main event for cell-mediated mech-
anisms of liver injury [4]. Kupffer cells, which are present in the
sinusoids and comprise around 2% of the liver, work by scaveng-
ing foreign material and secreting cytokines and proteases.
Finally, pit cells are natural killer cells present in the liver; these
are very rare and perform cytotoxic activity.
To understand liver pathology, it is necessary to briefly con-
sider the structure of the adult liver. This organ might appear
to be a mere pool of hepatocytes arranged within a low level
histological structure. However, the liver has a very complex
architecture organized around its basic unit, the liver lobule
(Fig. 1). The liver lobule [5] is a hexagonal-like structure sur-
rounding the central vein. Hepatocytes are arranged in arrays
one or two cells thick. Sinusoids are special blood vessels
formed between two arrays lined with sinusoidal cells connect-
ing the portal venous system to the systemic venous system.
Kupffer cells (liver-resident macrophages) are located in the
sinusoids, and portal triads are arranged around the lobule.
Triads consist of the termination of the portal vein branches,
hepatic artery branches, and a bile duct. Between two hepato-
cytes, small bile ducts constitute the first passage for bile exer-
tion by hepatocytes. Stellate cells are located in the space of
Disse, between the hepatocytes and the sinusoidal cells.
Toxicity mediated by drugs
Iron-induced hepatic toxicity
Thioacetamide-induced hepatic injury
Carbon tetrachloride toxicity
Hepatic fibrosis, cirrhosis, and portal
hypertension
A large number of molecules have been studied in
attempts to manage liver-related diseases. Many of these
drugs are of herbal origin and in some aspects they are still
not well characterized. Curcumin has long been used in
traditional medicine and research into this molecule has
increased considerably in recent years. The main aim of this
review is to summarize the most important actions of curcu-
min in liver diseases, focusing on its mechanism of action with
respect to various pathological conditions. As another chapter
of this book is devoted to curcumin and cancer, we will discuss
here mainly non-neoplastic liver diseases.
2. Liver Diseases
The basic etiologies of liver injuries are presented in Table 1.
2.1. Neoplastic Malignancies
Liver tumors, although not the most frequent, arouse great in-
terest. Research in this field expands continuously, and signifi-
cant advances are being achieved in diagnosis and treatment
[6]. Hepatocellular carcinoma is one of the most common such
malignancies and one of the principal complications in patients
with chronic liver disease or cirrhosis related to hepatitis B or

Vera-Ramirez et al. 89
 BioFactors

C virus infection [7,8]. Hepatoblastoma is a rare childhood ities in hepatocyte transport of bile constituents, due to gene
cancer that presents low rates of incidence and is difficult to alterations in synthesis or transporter mechanisms, such as
study. Nevertheless, different types and subtypes of hepato- progressive familial intrahepatic cholestasis syndrome, ATP8B1
blastoma have been identified [9,10]. Cholangiocarcinoma disease, or ABCB4 disease. Other syndromic forms of inherited
affects the biliary tract epithelium, and it may be present in in- cholestasis include intrahepatic biliary hypoplasia, familial
trahepatic or extrahepatic biliary ducts. Its incidence has hypercholanemia, or lymphedema-cholestasis syndrome [13].
increased in recent years, as have diagnostic mechanisms [11].
Primary hepatic angiosarcoma is a tumor of vascular endothe-
lial cell origin. This represents only 1.8% of all hepatic dis- 2.4. Nonalcoholic Fatty Liver Diseases
eases, and so it has not been as studied as much as other he- Nonalcoholic fatty liver diseases (NAFLD) range from hepatic
patic pathologies [12]. steatosis, the most clinically benign, through nonalcoholic stea-
tohepatitis (NASH), an intermediate lesion, to cirrhosis. Steato-
sis, NASH, fibrosis, and cirrhosis can result from metabolic
2.2. Alcohol-Related Disease
abnormalities and/or genetic predisposition, whereas NAFLD is
Alcoholism continues to affect ever more people worldwide,
associated with obesity, insulin resistance, and type 2 diabetes.
and it is a major cause of mortality in the United States and
Studies have suggested that obesity-related fatty liver disease is
Europe. In disease prediction, practically all cases involve fatty
related to metabolic syndrome [19,20]. NASH, the most widely
liver (known as steatosis), because of the excessive accumula-
studied NAFLD and which was first described as a clinical entity
tion of triglyceride in the hepatocytes. More than one in five
by Ludwig et al. [21], is a precursor to more severe liver dis-
alcoholics develop alcoholic hepatitis, and one-third of these
ease, and in almost 25% of patients it evolves into cirrhosis or
will suffer cirrhosis, which may develop to hepatocellular carci-
even hepatocellular carcinoma. In addition, it represents a fre-
noma, depending on the intensity and duration of alcohol
quent cause of abnormal liver test results in blood donors, and
intake, gender, and genetic and epigenetic factors that affect
is responsible for the asymptomatic elevation of serum amino-
alcohol metabolism and elimination in the liver. Alcoholic hepa-
transferases in over half of cases [22].
titis takes place because alcohol compromises the intestinal
The histological features of NASH have been well described,
barrier, leading to an increased presence of bacteria-derived li-
and in 1999, Brunt et al. [23] proposed a system to classify the
popolysaccharide (LPS) in the portal blood, which produces an
global assessment of necroinflammatory activity (grade) and fi-
excessive and dysregulated inflammatory response, resulting in
brosis with or without architectural remodeling (stage). This
hepatocyte injury and tissue necrosis [13,14]. One of the main
classification included three categories or grades of NASH nec-
alcohol effects on hepatocytes is oxidative stress. Ethanol indu-
roinflammation: grade 1 (mild), grade 2 (moderate), and grade
ces the generation of reactive oxygen substances (ROS) in hepa-
3 (severe), which correlate, respectively, with hepatocellular
tocytes, in the mitochondria, and also in cytosol, where free
steatosis, ballooning, and disarray, together with inflammation
iron is present together with enzymes such as xanthine oxidase
(acinar and portal). According to this classification, fibrosis is
and aldehyde oxidase. Besides ROS production, alcohol prod-
constituted of four categories (stages 1–4), depending on the
ucts can damage hepatocyte antioxidant defense components,
increase in connective tissue deposition and architectural
both enzymatic (such as superoxide dismutase, catalase, or glu-
remodeling. However, the pathogenesis of NASH is still not fully
tathione transferase) and nonenzymatic (principally metal-
understood. The theory currently most accepted is ‘‘the two-hit
binding proteins and vitamins) [13,14].
hypothesis,’’ proposed by Day and James [24]. The ‘‘first hit’’ is
the development of steatosis, following prolonged overnutrition
2.3. Hepatic Cholestasis
that deregulates the lipid metabolism and provokes an accumu-
Hepatic cholestasis refers to the situation of damaged bile
lation of free fatty acids (FFAs) and triglycerides in the liver.
secretion in the liver, characterized by the blockage of bile flow
The increased presence of FFAs in hepatocytes reduces b-oxi-
from the hepatocyte to the intestine, with the consequent accu-
dation, and thus enhances the accumulation of fatty acids. In
mulation of hydrophobic bile acids in the liver and plasma. Its
the ‘‘second hit,’’ steatosis progresses to inflammation and fi-
effects are commonly oxidative stress, increased apoptosis, and
brosis due to oxidative stress, mitochondrial dysfunction, and
fibrosis [15]. Hepatic cholestasis is strongly related to mitochon-
inflammatory cytokines, leading to liver cell inflammation and
drial dysfunction, because the mitochondria mediate death re-
necrosis, and activating the fibrogenic cascades [20,22,25].
ceptor signaling, contributing to oxidative damage and also to
fibrosis, whereas inflammation has been linked with apoptosis
[15]. Hepatic cholestasis is provoked by diverse inducing fac- 2.5. Human Hepatitis Viruses
tors, including drug treatment, bile duct ligation, and inherited There are five human hepatitis viruses, A–E, each with a dif-
and syndromic forms [16,17]. Experiments with rats have ferent development of infection. Hepatitis A and E are always
shown that bile duct ligation perturbs liver homeostasis, raising transient, whereas Hepatitis B, C, and delta may be either
levels of cytokines and signaling molecules; eventually, it may transient or chronic. Despite their differences, they all have
induce cirrhosis [18]. Inherited forms of intrahepatic cholestasis important features in common: their primary target of infec-
include disorders of primary bile acid synthesis and abnormal- tion is the hepatocyte, where they infect and replicate,

90 Curcumin and Liver Disease

although the mechanisms of viral infection and pathogenesis
vary depending on the hepatitis virus [13].
During the acute phase of hepatitis, for 2–6 weeks, many
hepatocytes are infected and viruses may enter the blood
stream or the bile canaliculi. In this acute phase, the immune
system attempts to eliminate the virus, primarily by antibodies
specifically directed against viral antigens. In a second step, in-
tracellular viruses are eliminated by the cellular immune
response, via the immune destruction of infected cells by cyto-
toxic T lymphocytes (CTLs). This second step can also be
achieved by noncytolytic elimination, by antiviral cytokines that
inhibit viral gene expression and replication, and which there-
fore do not need to destroy the infected cell. Chronic liver dis-
ease appears when the immune system fails to eliminate the vi-
rus infection [13]. Hepatitis B virus (HBV), hepatitis C virus
(HCV), and hepatitis delta virus (HDV) are potentially the most
harmful for the liver, being responsible for a large proportion of
liver failure conditions, such as fulminant hepatitis, cirrhosis,
and hepatocellular carcinoma [26]. HBV infection can be tran-
sient, in the form of acute hepatitis or fulminant hepatitis, or
develop to become chronic, leading to cirrhosis and/or hepato-
cellular carcinoma [27]. Regarding HCV, up to 75% of persons
infected progress to chronic hepatitis C. Most of these patients
are asymptomatic and present no physical signs of chronic liver
disease, other than fatigue. Chronic hepatitis C often progresses
to cirrhosis and hepatocellular carcinoma [7,13].
2.6. Hepatic Toxicity
More than 1,000 drugs can induce hepatic toxicity, and the risk
increases when the daily dose is higher than 50 mg or when the
liver is highly involved in metabolizing the drug. The principal
mechanism of drug-induced liver damage is that of mitochon-
drial dysfunction and lipid dysmetabolism, caused by the drug
itself and/or by the reactive metabolites generated. Mitochon-
drial dysfunction can have other harmful consequences, such
as oxidative stress, energy deficiency, steatosis by accumulation
of triglycerides, and cell death. In association with obesity and
diabetes, drugs may induce acute liver injury, steatosis, and
even steatohepatitis, which can lead to cirrhosis [28].
Another type of hepatic toxicity is iron induced. Iron is an
essential constituent of the body that participates in a large
number of biological reactions. It is present in functional form
in molecules such as cytochromes, hemoglobin, myoglobin,
and iron-dependent enzymes, and a good iron balance is nec-
essary to avoid diseases. Iron overload may be caused by a
wide range of acquired and hereditary conditions, such as he-
reditary hemochromatosis [29], and this condition is associated
with various toxic effects, of which the most common is liver
damage, with the excessive deposition of iron giving rise to fi-
brosis and cirrhosis [18].
The capacity of the liver to metabolize and help excrete
xenobiotics makes it very susceptible to damage, which may
be reversible but may also lead to fulminant hepatic failure
and death. The administration of high doses of thioacetamide
(TAA) to rats causes fibrosis, whereas cirrhosis is provoked by
Vera-Ramirez et al.
periodic lower doses, accompanied by high levels of ROS, the
production of proinflammatory molecules, and the activation
of HSCs [18,30].
In humans and animals, hepatotoxicity is the major out-
come of exposure to carbon tetrachloride (CCl4). Liver injury is
detectable by clinical signs (jaundice, swollen, and tender
liver), biochemical alterations (elevated levels of hepatic
enzymes in the blood and loss of enzymatic activities in the
liver), or histological examination (fatty degeneration and ne-
crosis of central hepatocytes, destruction of intracellular or-
ganelles, fibrosis, and cirrhosis). In the absence of clinical
signs, elevated levels of serum enzymes such as alanine ami-
notransferase (ALT), aspartate aminotransferase (AST), alka-
line phosphatase, and gamma glutamyl transferase may pro-
vide evidence of hepatocellular injury [31].
2.7. Hepatic Fibrosis, Cirrhosis, and Portal
Hypertension
Many of the above pathological conditions can lead to hepatic fi-
brosis and cirrhosis or are closely related to portal hyperten-
sion-related events. Fibrosis is characterized by an excessive
accumulation of extracellular matrix proteins, including colla-
gen. The main collagen-producing cells in the liver are HSCs,
which can be stimulated by ROS, inflammatory cytokines, and
apoptotic signals, among others. When this occurs, the hepatic
architecture is altered; a fibrous scar appears and nodules of
regenerating hepatocytes develop. If the damage continues, the
hepatic fibrosis advances to become hepatic cirrhosis, which
cannot be reversed. However, recent experimental findings sug-
gest that even advanced fibrosis may be reversible
[13,17,32,33]. Cirrhosis is the last pathological feature of
chronic hepatic injury and is characterized by the destruction of
the hepatic architecture and vascular structures, together with
blood flow failure due to the excessive deposition of collagen in
the cirrhotic liver, resulting from an imbalance between colla-
gen synthesis and degradation by membrane-bound metallopro-
teinase [17,32,33]. Portal hypertension in the liver is the hemo-
dynamic disorder that is most frequently associated with
cirrhosis. Cirrhosis causes distortion of the hepatic architecture,
followed by increased intrahepatic resistance and, finally, portal
hypertension, which is associated with other clinical pathologies
that may affect diverse organs. Such pathologies include diges-
tive hemorrhage, hypertensive gastropathy, hepatorenal and
hepatopulmonary syndromes, and alterations in the elimination
of drugs, microorganisms, and chemical substances by the liver
[13,34]. In addition to changes in liver architecture caused by
cirrhosis, the first step to portal hypertension is an increased re-
sistance to portal blood flow due to deficit and hyporesponse to
vasodilators, such as nitric oxide (NO), carbon monoxide (CO),
or hydrogen sulfide (H2S). The increased production of and
response to vasoconstrictors, such as endothelin, angiotensin II,
or alpha-adrenergic stimulus, also promotes hepatic vascular
resistance. This imbalance between excessive vasoconstrictors
and deficient vasodilators leads to an increase in portal blood
flow that aggravates portal hypertension [13].
91

3. Mechanisms Involved in Liver
Disease
Various in vitro and in vivo observations suggest that oxidative
stress and associated DNA, protein, and lipid damage may
underlie liver diseases as a key pathophysiological force and
which may also be related to chronic liver injury, hepatic
inflammation, and fibrosis [35].
Oxidative stress is a physiological consequence of the dis-
turbances in the oxidative balance caused by the interplay
between the production of free radicals and the activity of the
antioxidant defense system. Free radicals are inherent to aero-
bic life, and are produced and involved in important cellular
processes such as the immune response, vascular biology, thy-
roid hormone biosynthesis, and oxygen tension sensing. Conse-
quently, they are key mediators of physiological cell activity;
however, when the production of free radicals exceeds the
capacity of the antioxidant system to cope with oxidative cellu-
lar and tissue damage, oxidative stress occurs. Diverse conse-
quences arise from persistent oxidative stress, because free
radicals alter the chemical structure of any cell component but
they also play a crucial role in cell signaling as second mes-
sengers. Thus, an imbalance in the cellular and/or extracellu-
lar concentration of free radicals contributes significantly to
organ injury and dysfunction, and may ultimately lead to life-
threatening degenerative diseases [36].
Among the latter, non-neoplastic liver diseases secondary
to inflammation and fibrosis are evidently connected with
chronic oxidative stress. Liver fibrosis and its end-stage cirrho-
sis are the consequences of chronic liver injury of varied etiol-
ogy, including the liver diseases summarized in Section 2.
Proinflammatory insults originate from viral, toxic, metabolic,
or autoimmune processes and lead to the activation of HSCs,
which transdifferentiate from a quiescent lipid-storing pheno-
type to an a-smooth muscle actin (a-SMA) positive phenotype.
Activated HSCs are myofibroblast-like cells (MFs) that favor
extracellular matrix deposition materials, mainly collagen I, as
part of the liver’s wound healing mechanism. Portal fibroblasts
and bone marrow-derived mesenchymal stem cells are also
transdifferentiated into MFs by chronic liver injury. Together,
these cells originate a homogeneous proliferating, contractile,
and fibrogenic MF cell population regardless of its cellular ori-
gin, in terms of activation and functionality [37]. MFs also con-
tribute to liver fibrosis by releasing profibrogenic and proin-
flammatory cytokines and tissue inhibitors of metalloproteases
[38,39]. This progressive deposition of extracellular matrix
leads to hepatic structural and functional impairment.
3.1. Oxidative Stress and Inflammation
Among the mechanisms involved in mediating the process of
liver fibrosis, an important role is played by those mediated by
ROS, because persisting liver injury leading to parenchymal
damage and hepatocyte loss induces the recruitment of
immune effectors at the injured site. Activated resident
92
BioFactors
Kupffer cells and blood-derived neutrophils, monocytes/macro-
phages, and lymphocytes all release growth factors, cytokines,
chemokines, and ROS, which in turn activate HSCs into becom-
ing MFs [37,40].
Early MF activation involves the rapid induction of b plate-
let-derived growth factor (b-PDGF) receptor, the development
of a contractile and fibrogenic phenotype, and the modulation
of growth factor signaling. The autocrine PDGF loop is among
the most potent of all cytokine loops during HSC activation.
The union of PDGF with its b receptor activates focal adhesion
kinase (FAK), phosphatidylinositol 3-kinase (PI3K), and extrac-
ellular regulated kinase (ERK) signaling, and hence HSC prolif-
eration [41]. PDGF signaling is sustained through a positive
feedback mechanism that involves ROS. When the PDGF binds
to its receptor, PI3K and Rac are activated, and this in turn
activates nonphagocytic membrane NADPH-oxidase (NOX) and
ROS production. Among other mitogens that promote HSC pro-
liferation and activation through NOX activation, those of vas-
cular endothelial growth factor (VEGF), thrombin and its re-
ceptor, interleukin (IL)-1, epidermal growth factor (EGF),
angiotensin II (Ang II), and basic fibroblast growth factor
(bFGF) are very significant [42–44]. Other important mitogens
for HSCs are tumor necrosis factor a (TNFa) and IL-6, which
induce differentiation and activation of the HSCs through the
activation of a redox-sensitive transcription factor nuclear fac-
tor jb (NF-jb), which also plays a prominent role in liver
inflammation, as discussed below [44].
A second event in HSC activation involves migration to-
ward injury sites, driven by chemoattractants including PDGF
and VEGF, which induce the formation of cell protrusions
through protein kinase D1 [45], cytoskeletal reorganization
through protein kinase C (PKC) and Rho-dependent signaling
[46], CXCR3 ligands by activation of the Ras/ERK cascade [47],
and monocyte chemoattractant protein 1 (MCP-1) to recruit
and activate monocytes [48]. MCP-1 is mainly involved in the
formation and maintenance of the inflammatory infiltrate in
various wound-healing conditions, including chronic liver dis-
eases. MCP-1 is overexpressed by a wide range of hepatic cells
including injured hepatocytes [49], activated macrophages and
Kupffer cells, activated MFs, and activating HSCs [50] subse-
quent to the induction of redox transcription factors such as
NF-jb and activation protein 1 (AP-1) [51]. Although HSCs and
activated MFs play a significant role in chronic liver diseases
because of their highly fibrogenic activity, a wide variety of
immune and inflammatory cells are also recruited to injury
sites, forming the inflammatory infiltrate, including mononu-
clear cells, Kupffer cells, sinusoidal endothelial cells, platelets,
T-lymphocytes, and endothelial progenitor cells [52]. As men-
tioned above, mediators of oxidative stress, such as ROS and
other reactive species, may contribute to injury continuity, by
triggering and regulating the expression of proinflammatory
cytokines and chemokines in MFs and immune cells. The main
signaling pathway inducing this activity is mediated by the
activation of NF-jb, a major redox-sensitive transcription fac-
tor, which binds to specific DNA regions known as jb
Curcumin and Liver Disease
sequences and activates the expression of genes involved in
inflammation, cell survival, proliferation, and differentiation in
response to different stimuli, including the presence of free
radicals [53]. The injury-induced activation of hepatic NF-jb
promotes the production and secretion of TNFa, IL-6 in
Kupffer cells [52] and the expression of inducible NO synthase
(iNOS) and cycloxygenase-2 in monocytes [54]. Generally, any
cytokine capable of activating NF-jb is likely to induce ROS
generation, which further increases the inflammatory
response. On the other hand, oxidative products such as 4-
hydroxy-2,3-nonenal have been shown to upregulate the
expression of tumor growth factor (TGF-b1) in Kupffer and
macrophages [55] and to promote leukocyte chemotaxis [56].
Additionally, intrahepatic hypoxia may occur during inflamma-
tory and fibrotic processes, and indeed, the role of proangio-
genic cytokines and the expression of related receptors in liver
fibrosis is a determinant factor in advanced liver cirrhosis
[57]. At this stage, the role of injured hepatocytes, which are
prone to apoptosis and necrosis through mitochondrial impair-
ment and ROS release, is of crucial importance for injury per-
petuation and liver disease progression to cirrhosis.
3.2. Apoptosis
As mentioned above, with parenchymal damage and inflam-
matory signaling, the injury focus is a complex and highly
oxidative environment composed of inflammatory and angio-
genic cells releasing a wide variety of growth factors and
inflammatory cytokines and chemokines. Among the latter,
TNFa activates molecular pathways, which leads to either pro-
survival or to proapoptotic and necrotic signals, depending on
the redox state of the hepatocyte.
The interaction of TNFa with its type 1 receptor (TNFR1) is
followed by the association of the TNF-receptor-associated
death domain (TRADD), the Rieske iron-sulfur protein of
mitochondrial ubiquinol-cytochrome c reductase (RIP1), and
TNF-receptor-associated factors 2 and 5 (TRAF-2 and TRAF-5).
These interactions activate NF-jB and AP-1 transcription fac-
tors, which in turn activate the expression of genes that pro-
mote hepatocyte survival [58]. However, glutathione (GSH)
depletion alters the susceptibility of hepatocytes to TNF-a and
promotes the TNF-a-induced apoptosis axis, which finally leads
to mitochondrial dysfunction, promoting the overproduction of
ROS, impaired bioenergetics, severe oxidative stress, and cell
death [59,60]. Under these circumstances, the TRADD/RIP-1/
TRAF-2 complex can dissociate from TNRF1 and bind Fas-
ligand-associated death domain (FADD), recruiting caspase 8/
10, which cleaves the proapoptotic protein BH3 interacting do-
main death agonist (Bid). The cleaved tBid form translocates to
the mitochondria, producing the permeabilization of the mito-
chondrial outer membrane, the release of cytochrome c, and
the activation of the classic or intrinsic apoptosis pathway and
ROS production [41,61].
Alternatively, upon TNFa stimulation, RIP1 may be capable
of translocating to the mitochondria and permeabilizing the
mitochondrial outer membrane, thus eliciting ROS release,
Vera-Ramirez et al.
without cytochrome c release, provoking necrotic and caspase-
independent cell death [62] Upon these events, the ROS-medi-
ated and sustained activation of c-Jun amino-terminal kinases
(JNKs), through the oxidative inhibition of JNK phosphatases,
may also reinforce hepatocyte apoptosis [59].
Severe oxidative stress secondary to an acute inflamma-
tory response in liver injury may then provoke a molecular
shift that involves the transition from survival signals to death
signals in injured hepatocytes. This in turn releases further
ROS to the injury site, reinforcing the inflammatory response
and activating HSCs in a paracrine fashion. The result is a
chronic inflammatory process that contributes to perpetuate
fibrogenic progression through sustained MF activation.
3.3. Fibrogenesis
Fibrogenesis is the event preceding severe liver malfunction.
Activated MF cells produce and deposit large amounts of colla-
gen type I fibers and, to a much lesser but still significant
extent, collagen type III at the liver injury site. Fibrogenic ac-
tivity is mainly mediated by TGFb-1, which typically acts by
binding TGF-b type II receptors. Subsequent TGF-b type I acti-
vation and Smad protein association and phosphorylation
result in a heterodimeric complex that translocates to the nu-
cleus and binds to specific nucleotide motifs at the promoter
region of the collagen, type I, alpha 1 (COL1A1) gene [63].
Additionally, TGFb-1 induces the accumulation of hydrogen
peroxide (H2O2), which is involved in upregulating the expres-
sion of the COL1A1 gene through a CCAAT/enhancer binding
protein-b (C/EBPb)-dependent mechanism in MFs [64]. The
TGFb-1 fibrogenic signal is also mediated by connective tissue
growth factor (CTGF), which is normally expressed by MFs,
endothelial cells, and ductular epithelial cells but also by
parenchymal hepatocytes [65]. Moreover, CTGF expression in
parenchymal hepatocytes appears to be both TGFb-1-depend-
ent and TGFb-1-independent, and this process can also be up-
regulated by a wide variety of factors, including lipid peroxida-
tion products (hydroxynonenal and malondialdehyde) [66].
Finally, the contraction of active fibrogenic MFs may con-
tribute to intrahepatic resistance, portal hypertension, and lob-
ular distortion as fibrosis advances and cirrhosis develops. MF
contraction activity is mediated by both Caþ2-dependent mech-
anisms such as the myosin light chain kinase (MLCK) pathway,
and by Caþ2-sensitization mechanisms such as 17-kDa PKC-
potentiated protein phosphatase 1 inhibitor protein (CPI-17)
and myosin light chain phosphatase targeting subunit 1
(MYPT1) pathways [67].
From this summary of the most active and important sig-
naling pathways that intervene in liver fibrosis, it is possible to
envisage a highly oxidative environment in which an inducible
and complex cell population receives a wide range of signals
from the extracellular milieu, such as growth factors, cyto-
kines, and ROS or other reactive species, which promote
inflammatory and fibrogenic processes. In such a highly induc-
ible and oxidative microenvironment, immune and angiogenic
cells unavoidably increase their intracellular concentration of
93

ROS, which significantly affects cellular signaling pathways,
increasing disease severity and finally leading to liver degener-
ation and cirrhosis. In this sense, it is well known that protein
tyrosine phosphatases (PTPs) are susceptible to oxidation
because of chemical changes in the conserved cysteine residue
of their catalytic domain that possesses a low pKa. This reac-
tion inhibits phosphatase activity, and thus increases cytoplas-
mic protein kinase activity and stimulates the wide range of in-
tracellular signaling cascades that are mediated. Among these
molecular pathways, those initiated by inflammatory cytokines
and growth factors can be counted [68,69]. These important
changes affect MF and inflammatory cells, as well as hepato-
cytes, increasing profibrotic signaling and reinforcing ROS-
mediated signaling in a cyclic fashion. With respect to the lat-
ter, mitochondrial damage plays a pivotal role, acting as an
‘‘amplifying effecter’’ in a key stage of liver disease, and mak-
ing a major contribution to the transition from acute injury to
chronic damage through hepatocyte cell death and ROS
release.
3.4. Hyperlipemia
As stated above, a high level of circulating and hepatic FFAs
is a common cause of liver steatosis and steatohepatitis. Met-
abolic disturbances leading to steatosis (as associated with
obese or overweight patients and with metabolic syndrome,
and often including diabetes, insulin, and leptin resistance)
lead to a long-term accumulation of triglyceride in the hepa-
tocytes, coupled to ROS production, due to mitochondrial
impairment. This process is described in the ‘‘two hit’’ model
of NASH published by Day and James, which continues to be
widely accepted [24]. Mitochondrial dysfunction leads to
altered bioenergetics through the impairment of mitochon-
drial b-oxidation and FFA accumulation, which in turn induce
microsomal FFA oxidation (x-oxidation) involving cytochrome
P450 isoforms CYP2E1 and CYP4A to compensate for FFA
overload. CYP2E1 and CYP4A activity induces the production
of ROS, increasing intracellular oxidative stress and leading
to lipid peroxidation [70]. It has also been shown that ROS
generated by CYP2E1 activity promotes insulin resistance,
decreases insulin signaling in the liver, and increases hepatic
fat accumulation [71].
The mitochondrial b-oxidation of FFA continues in paral-
lel and it is not inhibited until massive electron flux on the
electron transport chain and ROS overproduction provoke
mitochondrial dysfunction. It has been shown that
mitochondrial lipotoxicity is not an early event due to hepatic
hyperlipidemia; indeed, initial transient increased mitochon-
drial activity has been reported in mice fed with hyperlipidic
diets; this is then followed by a significant decrease in oxida-
tive phosphorylation due to mitochondrial impairment
[72,73]. As mitochondrial oxidant capacity falls and ROS pro-
duction increases, lipids accumulate and lipid peroxidation
takes place, further increasing oxidative stress and cellular
damage. Under these highly stressing circumstances, mito-
chondrial uncoupling seems to take place. Uncoupling pro-
94
BioFactors
tein-2 (UCP-2) is thought to activate increasing proton leaks
across the mitochondrial inner membrane, reducing mito-
chondrial inner transmembrane potential (DWm) and oxida-
tive phosphorylation. This protective effect against ROS pro-
duction may in turn favor further triglyceride accumulation
in the hepatocytes. This topic remains controversial in mito-
chondrial bioenergetics, and further data are required to
clarify the question [74–76].
Many of these changes are mediated by the activation of
nuclear peroxisome proliferator-activated receptor-c (PPAR-c),
which promotes the expression of enzymes involved in lipid ca-
tabolism in the mitochondria and in the peroxisomes. Interest-
ingly, PPAR-c is activated by long-chain FFA, which may be
the cause of the observed rise in the expression of this tran-
scription factor in obesity and steatosis models [77,78].
Thus, defects in lipid homeostasis, bioenergetic impair-
ment, and the overproduction of ROS, leading to lipid accumu-
lation and oxidative stress due to severe hyperlipemia, all
induce massive hepatocyte apoptosis, which provokes an acute
inflammatory response, progressing to liver necrosis,
increased and chronic inflammation, and liver fibrosis. NASH
and NAFLD are classic examples of chronic liver diseases
induced by hyperlipemia.
4. Curcumin in Liver Diseases
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-
3,5-dione] is a natural yellow polyphenol extracted from the
rhizome of turmeric (Curcuma longa), a plant grown in tropi-
cal and subtropical regions throughout the world, which is
extensively used for food preparation in many Asian countries.
Besides its culinary use, curcumin has been considered a me-
dicinal herb in the traditional medicine of several countries for
centuries, because of to its antioxidant, anti-inflammatory,
antimutagenic, antimicrobial, and anticancer properties. How-
ever, the molecular network that governs curcumin-derived
effects on health has not been completely elucidated [79].
Numerous in vitro studies have indicated that curcumin
exerts potent antioxidant and anti-inflammatory properties,
which may account for its protective effect in chronic liver dis-
eases. Importantly, several in vivo studies from animal models
of chronic liver diseases have shown that curcumin possesses
antifibrogenic properties, mediated by the inactivation of dif-
ferent processes involved in liver damage [80].
Early experiments published by Matsuda et al. [81,82]
showed the hepatoprotective role of the main sesquiterpenes
isolated from the aqueous acetone extract of Zedoariae Rhi-
zoma, the rhizome of Curcuma zedoaria, in an acute liver
injury mouse model induced by D-galactosamine (D-GalN)/LPS
toxicity. In vitro and in vivo experiments suggested that curcu-
min may play a major role in hepatocytes protection by inhibi-
ting the production of NO and TNF-a in LPS-activated Kupffer
cells. Later studies using LPS-induced hepatotoxicity further
sustained these findings, highlighting the interfering role of
Curcumin and Liver Disease
curcumin on the inflammatory and apoptotic TNF-a/NF-jB sig-
naling pathway. Lukita-Atmadja et al. [83] showed that pre-
treatment with curcuminoids of endotoxemic BALB/C mice sig-
nificantly reduced the phagocytic activity of Kupffer cells and
suppressed the hepatic microvascular inflammatory response
to LPS. On the basis of their histopathologic observations and
previous experimental data, the authors hypothesized that cur-
cumin anti-inflammatory effects may be mediated by the inhi-
bition of the nuclear translocation of NF-jB and its dependent
proinflammatory cytokines, what may contribute to the signifi-
cant decrease in neutrophils recruitment to portal and central
venules as well as in the sinusoids of mice treated with curcu-
min with respect to control mice. Later on, Kaur et al. [84]
and Yun et al. [85] provided further insights into the molecular
mechanisms of curcumin-derived protection against LPS- and
LPS/GalN-induced liver injury, respectively, confirming the
involvement of TNF-a inhibition in these processes. Both works
reported that curcumin administration before induction with
GalN/LPS or LPS alone prevented the elevation in serum TNF-a
and aminotransferases, reduced hepatic necrosis, and inflam-
mation. Additionally, Kaur et al. confirmed the antioxidant
effect of curcumin by reporting decreased levels of lipid perox-
idation measured as thiobarbituric acid reactive substances
(TBARS) and increased GSH and SOD levels in the liver ho-
mogenates from LPS-challenged rats supplemented with cur-
cumin. In 2011, Cerný et al. [86] contributed with a work
showing that the ameliorative effects of curcumin on liver
injury in a rat LPS/dGalN model were also mediated by the
positive regulation of antioxidant and cytoprotective enzymes,
such as heme oxygenase-1 (HO-1). On the other hand, GalN/
LPS treatment dramatically increased lipid peroxidation levels,
NO production, and the expression of NO synthase 2 (NOS-2)
in the serum and liver of experimental animals. Curcumin-
derived hepatoprotection was evidenced through the decrease
in serum aminotransferases and the elevation of the expres-
sion and activity of HO and the acute drop in mRNA levels of
NOS-2, NO, both in plasma and liver, and liver CO, which is a
product of lipid peroxidation. Increases in plasma bilirubin
normally reflect the severity of hepatic injury upon hepatotoxic
GalN/LPS treatment, but, in this work, the authors argue that
further increases in the experimental group supplemented
with curcumin beyond those observed in rats not supple-
mented with curcumin are the consequence of HO-1 activity.
Interestingly, bilirubin is a potent antioxidant preventing lipid
peroxidation (which indeed demonstrated to be reduced upon
curcumin treatment). On the other hand, previous in vitro
studies using RAW264.7 macrophages have suggested that
HO-1 upregulation and the decrease in NO production are
mediated by the inhibitory effect of curcumin on NF-jB [87],
and the use of monocarbonyl analogs of curcumin has also
showed to decrease LPS-induced expression of TNF-a and IL-6
in mouse J774A.1 macrophages [88].
Apart from those works using LPS/dGalN-induced hepatitis
models, many other in vitro and in vivo experiments, per-
formed in a wide variety of liver injury models, have evidenced
Vera-Ramirez et al.
the protective activity of curcumin and confirmed the definitive
involvement of its effects on NF-jB signaling, which remain
paramount to our understanding of the potent hepatoprotec-
tive role of this herb-derived micronutrient.
Ramirez-Tortosa et al. [22] showed that curcumin supple-
mentation to experimental rabbits with high-fat-induced NASH
lowers the grade of NASH and aminotransferase activity, and
raises levels of mitochondrial antioxidants with respect to
healthy control animals. In addition to these changes, curcu-
min increased levels of mitochondrial antioxidants, reduced
mitochondrial reactive oxygen species, improved mitochon-
drial function, and lowered levels of TNF-a protein levels, thus
inhibiting the key apoptotic TNF-a-NF-jB axis in hepatocytes
during initial phases of the inflammatory infiltrate formation
followed by massive HSC activation and fibrosis. Curcumin
treatment has also been shown to decrease hepatic NF-jB lev-
els, markers of hepatic inflammation, and hepatomegaly in di-
abetic and obese mouse models [89]. A significant inhibition of
NF-jB activity is also the main mechanism by which curcumin
has been shown to preserve liver tissue integrity in early
stages of hepatic fibrosis in alcoholic liver injury rats [90]. In a
rat model of TAA-induced hepatotoxicity, curcumin has dem-
onstrated to improve the survival rates of the animals by sig-
nificantly inhibiting the nuclear binding of NF-jB and the iNOS
protein expression [91]. Novel formulations of curcumin, as
NanoCurcTM, showing enhanced bioavailability in liver tissue,
have rendered lower mRNA levels of TNF-a and IL-6 and
enhanced antioxidant capacity in liver tissue from mice
injected with CCl4 intraperitoneally [92]. Curcumin supplemen-
tation of mice fed with the methionine- and choline-deficient
diet, which develop steatohepatitis, also showed decreased NF-
jB activation and induction of downstream inflammatory cyto-
kines [93]. In vivo experiments with hamsters infected with
the trematode Opisthorchis viverrini, a liver fluke, and treated
with praziquantel have showed the induction of several inflam-
matory cytokines, namely NF-jB, and downstream effectors
such as TNF-a, IL-1b, iNOS, and COX-2, and enhanced levels
of oxidative stress, which are significantly ameliorated after
treatment with curcumin [94]. Experimental liver steatosis
induced by TNF-a injection in mice showed significant attenua-
tion after curcumin treatment reflected in decreased oxidative
stress, neutrophils infiltration, and improved histopathology
[95]. Taking into account the heterogeneous sources of liver
damage in the models employed by these studies and their in-
variable confluence on the molecular pathways affected by
curcumin in the reduction of damage, it should be pertinent to
conclude that the inhibition of the NF-jB plays a major role
regarding the hepatoprotective activity of curcumin, yet its
specific molecular mechanisms remain to be elucidated.
As mentioned before, besides TNF-a signaling, curcumin
has been reported to inhibit the expression of other NF-jB-
dependent inflammatory chemokines and cytokines, such as
IL-6, IL-2, TGF-b, and MCP-1, and inflammation-promoting
enzymes such as COX-2 and iNOS in Kupffer cells and hepatic
tissue homogenates [92,94,96,97]. Particularly, TGF-b is of
95

special interest during the latest phase of liver injury given its
involvement in liver fibrosis. In vivo studies using a bile duct li-
gation and CCl4 rat models have shown that curcumin is able
to partially inhibit the expression of TGF-b, significantly pre-
venting bile duct ligation fibrosis [98]. Using the rat HSC-T6
cell line, Lin et al. [99] showed that curcumin suppressed the
expression of SMA and collagen deposition in the HSC-T6 cells
after stimulation with TGF-b, accounting for its antifibrogenic
effects. Nevertheless, increased curcumin concentrations eli-
cited a different effect, as they induced HSC-T6 cells apoptosis.
Then, it has been suggested that curcumin exerts its hepato-
protective effects at this level through different and dose-de-
pendent mechanisms. This observation was further corrobo-
rated in vivo, through a study published shortly after by Shu
et al. [100] using a CCl4-induced liver injury rat model. Later,
Nakayama et al. [101] studied the molecular processes govern-
ing TGF-b-mediated liver fibrosis and curcumin injury preven-
tion using human Hep2G cells. This approach showed that
TGF-b induces the expression of plasminogen activator inhibi-
tor type-1 (PAI-1), a highly profibrotic molecule, through multi-
ple mechanisms involving NF-jB signaling and oxidative
stress. Interestingly, the authors argued that curcumin signifi-
cantly reduced PAI-1 expression, providing a mechanistic ex-
planation for the hepatoprotective effects of curcumin regard-
ing liver fibrosis. Additionally, curcumin has been related to a
significant reduction in liver fibrosis and injury induced by
both CCl4 and Concavalin A through the negative modulation
of the expression of Toll-like receptor (TLR) 2, TLR4, and
TLR9, providing further insights into the molecular processes
involved in liver pathogenesis [102,103].
Curcumin’s activity, which effectively modulates important
molecular pathways for cell biology and homeostasis, shows the
therapeutic potential of this widely appreciated micronutrient,
not only in the context of chronic liver diseases but also regard-
ing carcinogenesis and other age-related processes. Beyond to
its known attenuating role in inflammation and fibrosis signal-
ing, curcumin is well known to exert a potent antioxidant activ-
ity. Indeed, many of the works discussed above include the anal-
ysis of several oxidative stress and antioxidant markers to
further elucidate the molecular mechanisms by which curcumin
elicits its hepatoprotective activity.
Curcumin has been shown to improve both acute and sub-
acute liver injury induced by CCl4 intraperitoneal injection in
rats by lowering the activity of serum aminotransferases and
the levels of liver lipid peroxidation [104], reactivating the
impaired activity of important antioxidant enzymes, such as
hepatic SOD, lowering liver lipids and lipid peroxidation, and
increasing total GSH levels [105] Similarly, Pari et al. showed
that curcumin and tetrahydrocurcumin, one of the main prod-
ucts of curcumin catabolism, administered before chemical
induction of hepatocellular damage with erythromycin estolate
or chloroquine effectively reduce serum and hepatic levels of
lipid peroxides and TBARS together with a significant increase
in nonenzymatic and enzymatic antioxidants [106,107]. Impor-
tantly, curcumin is known to inhibit GSH depletion, which is
96
BioFactors
frequently observed in both experimental alcoholic liver dis-
ease and in CCl4-induced injury [108,109]. Increased levels of
catalase, glutathione peroxidase, and GSH are also restored
after curcumin supplementation in hepatocellular toxicity
models induced by cadmium [109,110] or paracetamol
[111,112].
Curcumin has been shown to decrease lipid storage in the
hepatocytes of high-fat diet rodents, contributing to minimize
the liver damage induced by mitochondrial dysfunction and
oxidative stress. Initial data regarding the hypolipemic activity
of curcumin were reported by Rao et al. [113], who showed
that rats fed concurrently with cholesterol and curcumin pre-
sented a lower cholesterol content in the liver than did rats
fed with cholesterol only. Later, Asai and Miyazawa [114]
showed that male Sprague-Dawley rats supplemented with 1.0
g curcuminoids/100 g diet registered significantly lower liver
triacylglycerol and cholesterol concentrations and significantly
higher hepatic acyl-CoA oxidase activity than did control rats
not given any curcumin supplement. This would account for
curcuminoids’ lipid-lowering potency in vivo. Rukkumani et al.
[115,116] assessed the hepatoprotective and hypolipemic
effects of curcumin and its synthetic analogs in a male rat
model of alcohol-induced and high-fat diet liver injury. In both
experiments, curcumin was shown to attenuate histopathologi-
cal changes in the liver and to reduce hepatic tissue levels of
cholesterol, triglycerides, and FFAs. More recently, Jang et al.
[117] showed that curcumin supplementation in a high-fat diet
in hamsters lowered levels of circulating lipids and hepatic lip-
ids. Significantly, they also showed that curcumin increased
fatty acid b-oxidation activity and reduced the activity of lipid
anabolic enzymes such as fatty acid synthase, 3-hydroxy-3-
methylglutaryl CoA reductase, and acyl CoA cholesterol acyl-
transferase. The latter property was also highlighted very
recently by Shao et al. as a molecular mechanism of curcumin
hepatoprotection [118]. Consequently, decreased levels of he-
patic lipid peroxides were detected in hamsters given a diet
supplemented with curcumin, with respect to control ham-
sters. Finally, curcumin has also been shown to significantly
inhibit the expression and activity of key proteins involved in
metabolism, such as hepatic protein tyrosine phosphatase 1B
(PTP1B), which is associated with defective insulin and leptin
signaling in a model of hypertriglyceridemia and hepatic stea-
tosis in fructose-fed rats [119], and leptin-like oxidized low-
density lipoprotein (LDL) receptor-1 (LOX-1) as a result of the
disruption of Wnt signaling and the activation of PPAR-c.
Reducing the expression of LOX-1, curcumin has been shown
to block the transport of extracellular ox-LDL into HSCs, thus
contributing to preventing their activation [120]. It seems clear
that curcumin exerts a hypolipidic effect, which prevents fatty
acid accumulation in the hepatocytes as a result of various
metabolic imbalances that finally lead to NASH.
Finally, very recent studies have reported that curcumin
also inhibits CYP2E1 activity [121], thus limiting ROS produc-
tion from microsomes, and activates NF-E2-related factor 2
(Nrf2) translocation to the nucleus, where it activates the
Curcumin and Liver Disease
expression of antioxidant enzymes [94,122], elevating the
expression of the apurinic/apyrimidinic endonuclease1/redox
factor-1 (APE1/Ref-1) DNA repair protein [97], and preventing
the activation of HSCs through PPAR-c overexpression, which
maintains lipid storing (quiescent) phenotype in these cells and
blocks PDGF and EGF signaling [123]. It also increases the
expression of mitochondrial biogenesis genes such as nuclear
respiratory factor 1 (NRF1) and mitochondrial transcription
factor A (Tfam) [124].
Regarding clinical studies assessing the hepatoprotective
activity of curcumin, there are limited data mainly related to
the study of its pharmacokinetics and toxicity [125]. Curcumin
is poorly absorbed following oral administration, as it is not
hydrosoluble, in such a way that the majority of the ingested
curcumin is excreted intact after passing through the digestive
tract. The rest is metabolized at the intestine mucosa and liver
rendering detectable curcumin plasma levels (0.41–1.75 lM af-
ter 1 h of oral dosing) when administered 4–8 g [126–128]. It
has been shown that curcumin absorption is greatly improved
by the concurrent oral administration of piperine from black
pepper [128]. In light of these observations, currently great
efforts are being made to improve curcumin bioavailability
and potentially study and exploit its therapeutic properties.
This way novel curcumin formulations and complexes are
being tested and include monocarbonyl analogs of curcumin
[87], polymeric nanoparticle formulations of curcumin
[92,129], and curcumin and phospholipids complexes [130]. On
the other hand, curcumin administration has been shown to
be fairly safe for humans even at high doses of 12 g/day [131].
Nevertheless, a recent study has pointed out the potential toxic
activity of several components of turmeric accompanying cur-
cumin from an in silico analysis [132], what deserves further
in vivo studies.
5. Conclusions
Curcumin is a highly pleiotropic and multiactivity molecule
that is capable of significantly affecting a wide variety of proc-
esses, ranging from the catalytic activity of antioxidant and
proinflammatory enzymes to the expression of multiple genes
related to inflammation and redox biology. Curcumin is a
micronutrient that is closely related to cellular redox balance
and thus to mitochondrial biology, making it the principal cell
organelle for cellular redox control. Not surprisingly, the prop-
erties and activity of curcumin give rise to a network of molec-
ular reactions that in every case and biological situation affect
the mitochondria. Fat accumulation is a key process in many
liver diseases, and various studies have shown that mitochon-
drial-related oxidative stress can be attenuated by specific die-
tary fat types, which in addition reduce blood lipids [133–136].
Therefore, the combined use of these dietary fats and curcu-
min would be an interesting approach to the treatment of liver
pathologies. Specific targeted therapies and/or agents for mito-
chondrial disorders and related diseases or degenerative proc-
Vera-Ramirez et al.
esses are extremely scarce, with many of them involving
severe side effects [137]. On the other hand, despite the proven
enormous therapeutic potential of curcumin and its safety for
human use, it has not yet been approved for use in the treat-
ment of any human disease. Therefore, future research into
mitochondrial dysfunction-associated diseases, such as chronic
liver disease, should focus on large, well-controlled human
studies to fully develop the therapeutic potential of this
micronutrient.
Acknowledgements
L. Vera-Ramirez was supported by a postdoctoral contract
from the Andalusian Regional government. P. Pe
rez-Lopez was
supported by a predoctoral FPI grant from the Spanish Minis-

pez was supported
try of Science and Innovation. A. Varela-Lo
by a predoctoral FPU grant from the Spanish Ministry of Sci-
ence and Innovation. The authors acknowledge the University
of Granada and the Andalusian Regional government for sup-
porting research of the group.
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