Review Article

Curcumin and Liver Disease Laura Vera-Ramirez1,2

Patricia P�erez-Lopez3

Alfonso Varela-Lopez3

MCarmen Ramirez-Tortosa4

Maurizio Battino5

Jos�e L. Quiles3*1GENyO Center Pfizer-University of Granada & Andalusian GovernmentCentre for Genomics & Oncology, Granada, Spain2Department of Oncology, Complejo Hospitalario de Jaen, Jaen, Spain3Institute of Nutrition and Food Technology ‘‘Jos�e Mataix Verd�u’’,Department of Physiology, University of Granada, Granada, Spain4Institute of Nutrition and Food Technology ‘‘Jos�e Mataix Verd�u’’,Department of Biochemistry and Molecular Biology II,University of Granada, Granada, Spain5Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche,Facolt�a di Medicina, Universit�a 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. VC 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 theworld. In Europe and North America, alcohol abuse and overnu-trition are the major causes of pathological conditions of theliver (with viral hepatitis increasing), whereas in Africa and

Asia, the main concerns are viral and parasitic infections. More-over, unlike other major causes of mortality, liver disease ratesare increasing rather than declining [1]. The liver is the largestinternal organ and it performs a great number of functions, sup-ported by its different cell types [2,3]. Hepatocytes, present atthe hepatic parenchyma, represent around 70% of the liver cellpopulation. Hepatocytes are implicated in the secretion of pro-teins and bile, in cholesterol metabolism, and in the metabolismof glucose and glycogen. Detoxification, the metabolism of urea,acute phase response, and blood clotting are other functionsperformed by hepatocytes. Cholangiocyte or bile duct cells arepresent in the duct epithelium and represent around 3% of theliver cell population. They transport bile, control the rate of bileflow, and secrete water and bicarbonate to control the pH ofbile. 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 thelobular parenchyma and form the sinusoidal plexus to facilitate

VC 2013 International Union of Biochemistry and Molecular Biology, Inc.Volume 39, Number 1, January/February 2013, Pages 88–100*Address for correspondence to: Jos�e L. Quiles, Ph.D., Instituto deNutrici�on y Tecnologıa de los Alimentos ‘‘Jos�e Mataix Verd�u’’, Universidadde Granada, Centro de Investigaci�on Biom�edica, Parque Tecnol�ogico deCiencias de la Salud, Lab. 120, Avenida del Conocimiento s/n, 18071Granada, Spain. Tel.:þ34 958241000, Ext. 20316; Fax:þ34 958241000 Ext.20316; E-mail: jlquiles@ugr.es.Received 30 July 2012; accepted 13 September 2012DOI: 10.1002/biof.1057Published online 10 January 2013 in Wiley Online Library(wileyonlinelibrary.com)

88 BioFactors

blood circulation. They also enable the transfer of moleculesand proteins between serum and hepatocytes, and are active inthe scavenging of macromolecular waste, in cytokine secretion,antigen presentation, and blood clotting. Hepatic stellate cells(HSCs) are situated in a perisinusoidal position and representaround 1.4% of liver cells. Their functions are the maintenance ofthe extracellular matrix, vitamin A storage, control of vasculartone, contribution of regenerative response to injury, thesecretion 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 thesinusoids 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; theseare 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 appearto be a mere pool of hepatocytes arranged within a low levelhistological structure. However, the liver has a very complexarchitecture 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 arraysone or two cells thick. Sinusoids are special blood vesselsformed 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 thesinusoids, 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 ofDisse, between the hepatocytes and the sinusoidal cells.

A large number of molecules have been studied inattempts to manage liver-related diseases. Many of thesedrugs are of herbal origin and in some aspects they are stillnot well characterized. Curcumin has long been used intraditional medicine and research into this molecule hasincreased considerably in recent years. The main aim of thisreview is to summarize the most important actions of curcu-min in liver diseases, focusing on its mechanism of action withrespect to various pathological conditions. As another chapterof this book is devoted to curcumin and cancer, we will discusshere mainly non-neoplastic liver diseases.

2. Liver Diseases

The basic etiologies of liver injuries are presented in Table 1.

2.1. Neoplastic MalignanciesLiver 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 suchmalignancies and one of the principal complications in patientswith chronic liver disease or cirrhosis related to hepatitis B or

The liver lobule.

Main liver diseases

Neoplastic liver

diseases

Hepatocellular carcinoma

Hepatoblastoma

Cholangiocarcinoma

Primary hepatic angiosarcoma

Non-neoplastic

liver diseases

Alcohol-related disease

Hepatic cholestasis

Nonalcoholic fatty liver diseases (NAFLD)

Nonalcoholic steatohepatitis (NASH)

Human hepatitis viruses

Hepatic toxicity

Toxicity mediated by drugs

Iron-induced hepatic toxicity

Thioacetamide-induced hepatic injury

Carbon tetrachloride toxicity

Hepatic fibrosis, cirrhosis, and portal

hypertension

FIG 1

TABLE 1

Vera-Ramirez et al. 89

C virus infection [7,8]. Hepatoblastoma is a rare childhoodcancer that presents low rates of incidence and is difficult tostudy. Nevertheless, different types and subtypes of hepato-blastoma have been identified [9,10]. Cholangiocarcinomaaffects the biliary tract epithelium, and it may be present in in-trahepatic or extrahepatic biliary ducts. Its incidence hasincreased 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-eases, and so it has not been as studied as much as other he-patic pathologies [12].

2.2. Alcohol-Related DiseaseAlcoholism continues to affect ever more people worldwide,and it is a major cause of mortality in the United States andEurope. In disease prediction, practically all cases involve fattyliver (known as steatosis), because of the excessive accumula-tion of triglyceride in the hepatocytes. More than one in fivealcoholics develop alcoholic hepatitis, and one-third of thesewill suffer cirrhosis, which may develop to hepatocellular carci-noma, depending on the intensity and duration of alcoholintake, gender, and genetic and epigenetic factors that affectalcohol metabolism and elimination in the liver. Alcoholic hepa-titis takes place because alcohol compromises the intestinalbarrier, leading to an increased presence of bacteria-derived li-popolysaccharide (LPS) in the portal blood, which produces anexcessive and dysregulated inflammatory response, resulting inhepatocyte injury and tissue necrosis [13,14]. One of the mainalcohol effects on hepatocytes is oxidative stress. Ethanol indu-ces the generation of reactive oxygen substances (ROS) in hepa-tocytes, in the mitochondria, and also in cytosol, where freeiron is present together with enzymes such as xanthine oxidaseand aldehyde oxidase. Besides ROS production, alcohol prod-ucts can damage hepatocyte antioxidant defense components,both enzymatic (such as superoxide dismutase, catalase, or glu-tathione transferase) and nonenzymatic (principally metal-binding proteins and vitamins) [13,14].

2.3. Hepatic CholestasisHepatic cholestasis refers to the situation of damaged bilesecretion in the liver, characterized by the blockage of bile flowfrom the hepatocyte to the intestine, with the consequent accu-mulation of hydrophobic bile acids in the liver and plasma. Itseffects are commonly oxidative stress, increased apoptosis, andfibrosis [15]. Hepatic cholestasis is strongly related to mitochon-drial dysfunction, because the mitochondria mediate death re-ceptor signaling, contributing to oxidative damage and also tofibrosis, whereas inflammation has been linked with apoptosis[15]. Hepatic cholestasis is provoked by diverse inducing fac-tors, including drug treatment, bile duct ligation, and inheritedand syndromic forms [16,17]. Experiments with rats haveshown that bile duct ligation perturbs liver homeostasis, raisinglevels of cytokines and signaling molecules; eventually, it mayinduce cirrhosis [18]. Inherited forms of intrahepatic cholestasisinclude disorders of primary bile acid synthesis and abnormal-

ities in hepatocyte transport of bile constituents, due to genealterations in synthesis or transporter mechanisms, such asprogressive familial intrahepatic cholestasis syndrome, ATP8B1disease, or ABCB4 disease. Other syndromic forms of inheritedcholestasis include intrahepatic biliary hypoplasia, familialhypercholanemia, or lymphedema-cholestasis syndrome [13].

2.4. Nonalcoholic Fatty Liver DiseasesNonalcoholic fatty liver diseases (NAFLD) range from hepaticsteatosis, the most clinically benign, through nonalcoholic stea-tohepatitis (NASH), an intermediate lesion, to cirrhosis. Steato-sis, NASH, fibrosis, and cirrhosis can result from metabolicabnormalities and/or genetic predisposition, whereas NAFLD isassociated with obesity, insulin resistance, and type 2 diabetes.Studies have suggested that obesity-related fatty liver disease isrelated to metabolic syndrome [19,20]. NASH, the most widelystudied NAFLD and which was first described as a clinical entityby Ludwig et al. [21], is a precursor to more severe liver dis-ease, and in almost 25% of patients it evolves into cirrhosis oreven hepatocellular carcinoma. In addition, it represents a fre-quent cause of abnormal liver test results in blood donors, andis responsible for the asymptomatic elevation of serum amino-transferases in over half of cases [22].

The histological features of NASH have been well described,and in 1999, Brunt et al. [23] proposed a system to classify theglobal assessment of necroinflammatory activity (grade) and fi-brosis with or without architectural remodeling (stage). Thisclassification included three categories or grades of NASH nec-roinflammation: grade 1 (mild), grade 2 (moderate), and grade3 (severe), which correlate, respectively, with hepatocellularsteatosis, ballooning, and disarray, together with inflammation(acinar and portal). According to this classification, fibrosis isconstituted of four categories (stages 1–4), depending on theincrease in connective tissue deposition and architecturalremodeling. However, the pathogenesis of NASH is still not fullyunderstood. The theory currently most accepted is ‘‘the two-hithypothesis,’’ proposed by Day and James [24]. The ‘‘first hit’’ isthe development of steatosis, following prolonged overnutritionthat deregulates the lipid metabolism and provokes an accumu-lation of free fatty acids (FFAs) and triglycerides in the liver.The increased presence of FFAs in hepatocytes reduces b-oxi-dation, and thus enhances the accumulation of fatty acids. Inthe ‘‘second hit,’’ steatosis progresses to inflammation and fi-brosis due to oxidative stress, mitochondrial dysfunction, andinflammatory cytokines, leading to liver cell inflammation andnecrosis, and activating the fibrogenic cascades [20,22,25].

2.5. Human Hepatitis VirusesThere are five human hepatitis viruses, A–E, each with a dif-ferent development of infection. Hepatitis A and E are alwaystransient, whereas Hepatitis B, C, and delta may be eithertransient or chronic. Despite their differences, they all haveimportant features in common: their primary target of infec-tion is the hepatocyte, where they infect and replicate,

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90 Curcumin and Liver Disease

although the mechanisms of viral infection and pathogenesisvary depending on the hepatitis virus [13].

During the acute phase of hepatitis, for 2–6 weeks, manyhepatocytes are infected and viruses may enter the bloodstream or the bile canaliculi. In this acute phase, the immunesystem attempts to eliminate the virus, primarily by antibodiesspecifically directed against viral antigens. In a second step, in-tracellular viruses are eliminated by the cellular immuneresponse, via the immune destruction of infected cells by cyto-toxic T lymphocytes (CTLs). This second step can also beachieved by noncytolytic elimination, by antiviral cytokines thatinhibit 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 mostharmful for the liver, being responsible for a large proportion ofliver 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, ordevelop to become chronic, leading to cirrhosis and/or hepato-cellular carcinoma [27]. Regarding HCV, up to 75% of personsinfected progress to chronic hepatitis C. Most of these patientsare asymptomatic and present no physical signs of chronic liverdisease, other than fatigue. Chronic hepatitis C often progressesto cirrhosis and hepatocellular carcinoma [7,13].

2.6. Hepatic ToxicityMore than 1,000 drugs can induce hepatic toxicity, and the riskincreases when the daily dose is higher than 50 mg or when theliver is highly involved in metabolizing the drug. The principalmechanism of drug-induced liver damage is that of mitochon-drial dysfunction and lipid dysmetabolism, caused by the drugitself and/or by the reactive metabolites generated. Mitochon-drial dysfunction can have other harmful consequences, suchas oxidative stress, energy deficiency, steatosis by accumulationof triglycerides, and cell death. In association with obesity anddiabetes, drugs may induce acute liver injury, steatosis, andeven steatohepatitis, which can lead to cirrhosis [28].

Another type of hepatic toxicity is iron induced. Iron is anessential constituent of the body that participates in a largenumber of biological reactions. It is present in functional formin 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 awide range of acquired and hereditary conditions, such as he-reditary hemochromatosis [29], and this condition is associatedwith various toxic effects, of which the most common is liverdamage, with the excessive deposition of iron giving rise to fi-brosis and cirrhosis [18].

The capacity of the liver to metabolize and help excretexenobiotics makes it very susceptible to damage, which maybe reversible but may also lead to fulminant hepatic failureand death. The administration of high doses of thioacetamide(TAA) to rats causes fibrosis, whereas cirrhosis is provoked by

periodic lower doses, accompanied by high levels of ROS, theproduction of proinflammatory molecules, and the activationof HSCs [18,30].

In humans and animals, hepatotoxicity is the major out-come of exposure to carbon tetrachloride (CCl4). Liver injury isdetectable by clinical signs (jaundice, swollen, and tenderliver), biochemical alterations (elevated levels of hepaticenzymes in the blood and loss of enzymatic activities in theliver), or histological examination (fatty degeneration and ne-crosis of central hepatocytes, destruction of intracellular or-ganelles, fibrosis, and cirrhosis). In the absence of clinicalsigns, 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 PortalHypertensionMany 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 excessiveaccumulation 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, andapoptotic signals, among others. When this occurs, the hepaticarchitecture is altered; a fibrous scar appears and nodules ofregenerating hepatocytes develop. If the damage continues, thehepatic fibrosis advances to become hepatic cirrhosis, whichcannot 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 ofchronic hepatic injury and is characterized by the destruction ofthe hepatic architecture and vascular structures, together withblood flow failure due to the excessive deposition of collagen inthe 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 withcirrhosis. Cirrhosis causes distortion of the hepatic architecture,followed by increased intrahepatic resistance and, finally, portalhypertension, which is associated with other clinical pathologiesthat may affect diverse organs. Such pathologies include diges-tive hemorrhage, hypertensive gastropathy, hepatorenal andhepatopulmonary syndromes, and alterations in the eliminationof drugs, microorganisms, and chemical substances by the liver[13,34]. In addition to changes in liver architecture caused bycirrhosis, the first step to portal hypertension is an increased re-sistance to portal blood flow due to deficit and hyporesponse tovasodilators, such as nitric oxide (NO), carbon monoxide (CO),or hydrogen sulfide (H2S). The increased production of andresponse to vasoconstrictors, such as endothelin, angiotensin II,or alpha-adrenergic stimulus, also promotes hepatic vascularresistance. This imbalance between excessive vasoconstrictorsand deficient vasodilators leads to an increase in portal bloodflow that aggravates portal hypertension [13].

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3. Mechanisms Involved in LiverDisease

Various in vitro and in vivo observations suggest that oxidativestress and associated DNA, protein, and lipid damage mayunderlie liver diseases as a key pathophysiological force andwhich may also be related to chronic liver injury, hepaticinflammation, and fibrosis [35].

Oxidative stress is a physiological consequence of the dis-turbances in the oxidative balance caused by the interplaybetween the production of free radicals and the activity of theantioxidant defense system. Free radicals are inherent to aero-bic life, and are produced and involved in important cellularprocesses 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 thecapacity 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 freeradicals alter the chemical structure of any cell component butthey 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 toorgan injury and dysfunction, and may ultimately lead to life-threatening degenerative diseases [36].

Among the latter, non-neoplastic liver diseases secondaryto inflammation and fibrosis are evidently connected withchronic 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 favorextracellular matrix deposition materials, mainly collagen I, aspart of the liver’s wound healing mechanism. Portal fibroblastsand bone marrow-derived mesenchymal stem cells are alsotransdifferentiated 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 matrixleads to hepatic structural and functional impairment.

3.1. Oxidative Stress and InflammationAmong the mechanisms involved in mediating the process ofliver fibrosis, an important role is played by those mediated byROS, because persisting liver injury leading to parenchymaldamage and hepatocyte loss induces the recruitment ofimmune effectors at the injured site. Activated resident

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 developmentof a contractile and fibrogenic phenotype, and the modulationof growth factor signaling. The autocrine PDGF loop is amongthe most potent of all cytokine loops during HSC activation.The union of PDGF with its b receptor activates focal adhesionkinase (FAK), phosphatidylinositol 3-kinase (PI3K), and extrac-ellular regulated kinase (ERK) signaling, and hence HSC prolif-eration [41]. PDGF signaling is sustained through a positivefeedback mechanism that involves ROS. When the PDGF bindsto its receptor, PI3K and Rac are activated, and this in turnactivates nonphagocytic membrane NADPH-oxidase (NOX) andROS 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 mitogensfor HSCs are tumor necrosis factor a (TNFa) and IL-6, whichinduce differentiation and activation of the HSCs through theactivation of a redox-sensitive transcription factor nuclear fac-tor jb (NF-jb), which also plays a prominent role in liverinflammation, as discussed below [44].

A second event in HSC activation involves migration to-ward injury sites, driven by chemoattractants including PDGFand VEGF, which induce the formation of cell protrusionsthrough protein kinase D1 [45], cytoskeletal reorganizationthrough 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 recruitand activate monocytes [48]. MCP-1 is mainly involved in theformation and maintenance of the inflammatory infiltrate invarious wound-healing conditions, including chronic liver dis-eases. MCP-1 is overexpressed by a wide range of hepatic cellsincluding injured hepatocytes [49], activated macrophages andKupffer cells, activated MFs, and activating HSCs [50] subse-quent to the induction of redox transcription factors such asNF-jb and activation protein 1 (AP-1) [51]. Although HSCs andactivated MFs play a significant role in chronic liver diseasesbecause of their highly fibrogenic activity, a wide variety ofimmune and inflammatory cells are also recruited to injurysites, 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 andother reactive species, may contribute to injury continuity, bytriggering and regulating the expression of proinflammatorycytokines and chemokines in MFs and immune cells. The mainsignaling pathway inducing this activity is mediated by theactivation of NF-jb, a major redox-sensitive transcription fac-tor, which binds to specific DNA regions known as jb

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92 Curcumin and Liver Disease

sequences and activates the expression of genes involved ininflammation, cell survival, proliferation, and differentiation inresponse to different stimuli, including the presence of freeradicals [53]. The injury-induced activation of hepatic NF-jbpromotes the production and secretion of TNFa, IL-6 inKupffer cells [52] and the expression of inducible NO synthase(iNOS) and cycloxygenase-2 in monocytes [54]. Generally, anycytokine capable of activating NF-jb is likely to induce ROSgeneration, which further increases the inflammatoryresponse. On the other hand, oxidative products such as 4-hydroxy-2,3-nonenal have been shown to upregulate theexpression of tumor growth factor (TGF-b1) in Kupffer andmacrophages [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 liverfibrosis is a determinant factor in advanced liver cirrhosis[57]. At this stage, the role of injured hepatocytes, which areprone 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. ApoptosisAs mentioned above, with parenchymal damage and inflam-matory signaling, the injury focus is a complex and highlyoxidative environment composed of inflammatory and angio-genic cells releasing a wide variety of growth factors andinflammatory cytokines and chemokines. Among the latter,TNFa activates molecular pathways, which leads to either pro-survival or to proapoptotic and necrotic signals, depending onthe redox state of the hepatocyte.

The interaction of TNFa with its type 1 receptor (TNFR1) isfollowed by the association of the TNF-receptor-associateddeath domain (TRADD), the Rieske iron-sulfur protein ofmitochondrial ubiquinol-cytochrome c reductase (RIP1), andTNF-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 andpromotes the TNF-a-induced apoptosis axis, which finally leadsto mitochondrial dysfunction, promoting the overproduction ofROS, impaired bioenergetics, severe oxidative stress, and celldeath [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 tothe mitochondria, producing the permeabilization of the mito-chondrial outer membrane, the release of cytochrome c, andthe activation of the classic or intrinsic apoptosis pathway andROS production [41,61].

Alternatively, upon TNFa stimulation, RIP1 may be capableof translocating to the mitochondria and permeabilizing themitochondrial outer membrane, thus eliciting ROS release,

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 molecularshift that involves the transition from survival signals to deathsignals in injured hepatocytes. This in turn releases furtherROS to the injury site, reinforcing the inflammatory responseand activating HSCs in a paracrine fashion. The result is achronic inflammatory process that contributes to perpetuatefibrogenic progression through sustained MF activation.

3.3. FibrogenesisFibrogenesis 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 significantextent, collagen type III at the liver injury site. Fibrogenic ac-tivity is mainly mediated by TGFb-1, which typically acts bybinding TGF-b type II receptors. Subsequent TGF-b type I acti-vation and Smad protein association and phosphorylationresult in a heterodimeric complex that translocates to the nu-cleus and binds to specific nucleotide motifs at the promoterregion of the collagen, type I, alpha 1 (COL1A1) gene [63].Additionally, TGFb-1 induces the accumulation of hydrogenperoxide (H2O2), which is involved in upregulating the expres-sion of the COL1A1 gene through a CCAAT/enhancer bindingprotein-b (C/EBPb)-dependent mechanism in MFs [64]. TheTGFb-1 fibrogenic signal is also mediated by connective tissuegrowth factor (CTGF), which is normally expressed by MFs,endothelial cells, and ductular epithelial cells but also byparenchymal hepatocytes [65]. Moreover, CTGF expression inparenchymal 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. MFcontraction 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 toenvisage a highly oxidative environment in which an inducibleand complex cell population receives a wide range of signalsfrom the extracellular milieu, such as growth factors, cyto-kines, and ROS or other reactive species, which promoteinflammatory and fibrogenic processes. In such a highly induc-ible and oxidative microenvironment, immune and angiogeniccells unavoidably increase their intracellular concentration of

Vera-Ramirez et al. 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 proteintyrosine phosphatases (PTPs) are susceptible to oxidationbecause of chemical changes in the conserved cysteine residueof 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 thesemolecular pathways, those initiated by inflammatory cytokinesand growth factors can be counted [68,69]. These importantchanges 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 tochronic damage through hepatocyte cell death and ROSrelease.

3.4. HyperlipemiaAs stated above, a high level of circulating and hepatic FFAsis a common cause of liver steatosis and steatohepatitis. Met-abolic disturbances leading to steatosis (as associated withobese 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 mitochondrialimpairment. This process is described in the ‘‘two hit’’ modelof NASH published by Day and James, which continues to bewidely accepted [24]. Mitochondrial dysfunction leads toaltered bioenergetics through the impairment of mitochon-drial b-oxidation and FFA accumulation, which in turn inducemicrosomal FFA oxidation (x-oxidation) involving cytochromeP450 isoforms CYP2E1 and CYP4A to compensate for FFAoverload. CYP2E1 and CYP4A activity induces the productionof ROS, increasing intracellular oxidative stress and leadingto lipid peroxidation [70]. It has also been shown that ROSgenerated by CYP2E1 activity promotes insulin resistance,decreases insulin signaling in the liver, and increases hepaticfat accumulation [71].

The mitochondrial b-oxidation of FFA continues in paral-lel and it is not inhibited until massive electron flux on theelectron transport chain and ROS overproduction provokemitochondrial dysfunction. It has been shown thatmitochondrial lipotoxicity is not an early event due to hepatichyperlipidemia; indeed, initial transient increased mitochon-drial activity has been reported in mice fed with hyperlipidicdiets; 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 peroxidationtakes place, further increasing oxidative stress and cellulardamage. Under these highly stressing circumstances, mito-chondrial uncoupling seems to take place. Uncoupling pro-

tein-2 (UCP-2) is thought to activate increasing proton leaksacross 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 accumulationin the hepatocytes. This topic remains controversial in mito-chondrial bioenergetics, and further data are required toclarify the question [74–76].

Many of these changes are mediated by the activation ofnuclear 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 bethe 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, allinduce massive hepatocyte apoptosis, which provokes an acuteinflammatory response, progressing to liver necrosis,increased and chronic inflammation, and liver fibrosis. NASHand NAFLD are classic examples of chronic liver diseasesinduced 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 therhizome of turmeric (Curcuma longa), a plant grown in tropi-cal and subtropical regions throughout the world, which isextensively 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 forcenturies, because of to its antioxidant, anti-inflammatory,antimutagenic, antimicrobial, and anticancer properties. How-ever, the molecular network that governs curcumin-derivedeffects on health has not been completely elucidated [79].

Numerous in vitro studies have indicated that curcuminexerts 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 modelsof chronic liver diseases have shown that curcumin possessesantifibrogenic 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 sesquiterpenesisolated from the aqueous acetone extract of Zedoariae Rhi-zoma, the rhizome of Curcuma zedoaria, in an acute liverinjury mouse model induced by D-galactosamine (D-GalN)/LPStoxicity. 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 Kupffercells. Later studies using LPS-induced hepatotoxicity furthersustained these findings, highlighting the interfering role of

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94 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 andsuppressed the hepatic microvascular inflammatory responseto LPS. On the basis of their histopathologic observations andprevious 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 dependentproinflammatory cytokines, what may contribute to the signifi-cant decrease in neutrophils recruitment to portal and centralvenules 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 molecularmechanisms of curcumin-derived protection against LPS- andLPS/GalN-induced liver injury, respectively, confirming theinvolvement of TNF-a inhibition in these processes. Both worksreported that curcumin administration before induction withGalN/LPS or LPS alone prevented the elevation in serum TNF-aand aminotransferases, reduced hepatic necrosis, and inflam-mation. Additionally, Kaur et al. confirmed the antioxidanteffect 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, Cerny et al. [86] contributed with a workshowing that the ameliorative effects of curcumin on liverinjury in a rat LPS/dGalN model were also mediated by thepositive 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 decreasein serum aminotransferases and the elevation of the expres-sion and activity of HO and the acute drop in mRNA levels ofNOS-2, NO, both in plasma and liver, and liver CO, which is aproduct of lipid peroxidation. Increases in plasma bilirubinnormally reflect the severity of hepatic injury upon hepatotoxicGalN/LPS treatment, but, in this work, the authors argue thatfurther increases in the experimental group supplementedwith 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 lipidperoxidation (which indeed demonstrated to be reduced uponcurcumin treatment). On the other hand, previous in vitrostudies using RAW264.7 macrophages have suggested thatHO-1 upregulation and the decrease in NO production aremediated by the inhibitory effect of curcumin on NF-jB [87],and the use of monocarbonyl analogs of curcumin has alsoshowed to decrease LPS-induced expression of TNF-a and IL-6in mouse J774A.1 macrophages [88].

Apart from those works using LPS/dGalN-induced hepatitismodels, many other in vitro and in vivo experiments, per-formed in a wide variety of liver injury models, have evidenced

the protective activity of curcumin and confirmed the definitiveinvolvement of its effects on NF-jB signaling, which remainparamount 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 NASHlowers the grade of NASH and aminotransferase activity, andraises levels of mitochondrial antioxidants with respect tohealthy control animals. In addition to these changes, curcu-min increased levels of mitochondrial antioxidants, reducedmitochondrial reactive oxygen species, improved mitochon-drial function, and lowered levels of TNF-a protein levels, thusinhibiting the key apoptotic TNF-a-NF-jB axis in hepatocytesduring initial phases of the inflammatory infiltrate formationfollowed by massive HSC activation and fibrosis. Curcumintreatment 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 ofNF-jB activity is also the main mechanism by which curcuminhas been shown to preserve liver tissue integrity in earlystages of hepatic fibrosis in alcoholic liver injury rats [90]. In arat 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 iNOSprotein expression [91]. Novel formulations of curcumin, asNanoCurcTM, showing enhanced bioavailability in liver tissue,have rendered lower mRNA levels of TNF-a and IL-6 andenhanced antioxidant capacity in liver tissue from miceinjected with CCl4 intraperitoneally [92]. Curcumin supplemen-tation of mice fed with the methionine- and choline-deficientdiet, which develop steatohepatitis, also showed decreased NF-jB activation and induction of downstream inflammatory cyto-kines [93]. In vivo experiments with hamsters infected withthe trematode Opisthorchis viverrini, a liver fluke, and treatedwith praziquantel have showed the induction of several inflam-matory cytokines, namely NF-jB, and downstream effectorssuch as TNF-a, IL-1b, iNOS, and COX-2, and enhanced levelsof oxidative stress, which are significantly ameliorated aftertreatment with curcumin [94]. Experimental liver steatosisinduced by TNF-a injection in mice showed significant attenua-tion after curcumin treatment reflected in decreased oxidativestress, neutrophils infiltration, and improved histopathology[95]. Taking into account the heterogeneous sources of liverdamage in the models employed by these studies and their in-variable confluence on the molecular pathways affected bycurcumin in the reduction of damage, it should be pertinent toconclude that the inhibition of the NF-jB plays a major roleregarding the hepatoprotective activity of curcumin, yet itsspecific molecular mechanisms remain to be elucidated.

As mentioned before, besides TNF-a signaling, curcuminhas been reported to inhibit the expression of other NF-jB-dependent inflammatory chemokines and cytokines, such asIL-6, IL-2, TGF-b, and MCP-1, and inflammation-promotingenzymes such as COX-2 and iNOS in Kupffer cells and hepatictissue homogenates [92,94,96,97]. Particularly, TGF-b is of

Vera-Ramirez et al. 95

special interest during the latest phase of liver injury given itsinvolvement in liver fibrosis. In vivo studies using a bile duct li-gation and CCl4 rat models have shown that curcumin is ableto partially inhibit the expression of TGF-b, significantly pre-venting bile duct ligation fibrosis [98]. Using the rat HSC-T6cell line, Lin et al. [99] showed that curcumin suppressed theexpression of SMA and collagen deposition in the HSC-T6 cellsafter stimulation with TGF-b, accounting for its antifibrogeniceffects. 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 Shuet 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 thatTGF-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 oxidativestress. 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 asignificant reduction in liver fibrosis and injury induced byboth CCl4 and Concavalin A through the negative modulationof the expression of Toll-like receptor (TLR) 2, TLR4, andTLR9, providing further insights into the molecular processesinvolved in liver pathogenesis [102,103].

Curcumin’s activity, which effectively modulates importantmolecular pathways for cell biology and homeostasis, shows thetherapeutic 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 toits 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 tofurther elucidate the molecular mechanisms by which curcuminelicits its hepatoprotective activity.

Curcumin has been shown to improve both acute and sub-acute liver injury induced by CCl4 intraperitoneal injection inrats by lowering the activity of serum aminotransferases andthe levels of liver lipid peroxidation [104], reactivating theimpaired activity of important antioxidant enzymes, such ashepatic SOD, lowering liver lipids and lipid peroxidation, andincreasing total GSH levels [105] Similarly, Pari et al. showedthat curcumin and tetrahydrocurcumin, one of the main prod-ucts of curcumin catabolism, administered before chemicalinduction of hepatocellular damage with erythromycin estolateor chloroquine effectively reduce serum and hepatic levels oflipid peroxides and TBARS together with a significant increasein nonenzymatic and enzymatic antioxidants [106,107]. Impor-tantly, curcumin is known to inhibit GSH depletion, which is

frequently observed in both experimental alcoholic liver dis-ease and in CCl4-induced injury [108,109]. Increased levels ofcatalase, glutathione peroxidase, and GSH are also restoredafter curcumin supplementation in hepatocellular toxicitymodels induced by cadmium [109,110] or paracetamol[111,112].

Curcumin has been shown to decrease lipid storage in thehepatocytes of high-fat diet rodents, contributing to minimizethe liver damage induced by mitochondrial dysfunction andoxidative stress. Initial data regarding the hypolipemic activityof curcumin were reported by Rao et al. [113], who showedthat rats fed concurrently with cholesterol and curcumin pre-sented a lower cholesterol content in the liver than did ratsfed with cholesterol only. Later, Asai and Miyazawa [114]showed that male Sprague-Dawley rats supplemented with 1.0g curcuminoids/100 g diet registered significantly lower livertriacylglycerol and cholesterol concentrations and significantlyhigher hepatic acyl-CoA oxidase activity than did control ratsnot given any curcumin supplement. This would account forcurcuminoids’ lipid-lowering potency in vivo. Rukkumani et al.[115,116] assessed the hepatoprotective and hypolipemiceffects of curcumin and its synthetic analogs in a male ratmodel of alcohol-induced and high-fat diet liver injury. In bothexperiments, curcumin was shown to attenuate histopathologi-cal changes in the liver and to reduce hepatic tissue levels ofcholesterol, triglycerides, and FFAs. More recently, Jang et al.[117] showed that curcumin supplementation in a high-fat dietin hamsters lowered levels of circulating lipids and hepatic lip-ids. Significantly, they also showed that curcumin increasedfatty acid b-oxidation activity and reduced the activity of lipidanabolic enzymes such as fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase, and acyl CoA cholesterol acyl-transferase. The latter property was also highlighted veryrecently by Shao et al. as a molecular mechanism of curcuminhepatoprotection [118]. Consequently, decreased levels of he-patic lipid peroxides were detected in hamsters given a dietsupplemented with curcumin, with respect to control ham-sters. Finally, curcumin has also been shown to significantlyinhibit the expression and activity of key proteins involved inmetabolism, such as hepatic protein tyrosine phosphatase 1B(PTP1B), which is associated with defective insulin and leptinsignaling 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 thedisruption of Wnt signaling and the activation of PPAR-c.Reducing the expression of LOX-1, curcumin has been shownto block the transport of extracellular ox-LDL into HSCs, thuscontributing to preventing their activation [120]. It seems clearthat curcumin exerts a hypolipidic effect, which prevents fattyacid accumulation in the hepatocytes as a result of variousmetabolic imbalances that finally lead to NASH.

Finally, very recent studies have reported that curcuminalso 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

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96 Curcumin and Liver Disease

expression of antioxidant enzymes [94,122], elevating theexpression of the apurinic/apyrimidinic endonuclease1/redoxfactor-1 (APE1/Ref-1) DNA repair protein [97], and preventingthe activation of HSCs through PPAR-c overexpression, whichmaintains lipid storing (quiescent) phenotype in these cells andblocks PDGF and EGF signaling [123]. It also increases theexpression of mitochondrial biogenesis genes such as nuclearrespiratory factor 1 (NRF1) and mitochondrial transcriptionfactor A (Tfam) [124].

Regarding clinical studies assessing the hepatoprotectiveactivity of curcumin, there are limited data mainly related tothe study of its pharmacokinetics and toxicity [125]. Curcuminis poorly absorbed following oral administration, as it is nothydrosoluble, in such a way that the majority of the ingestedcurcumin is excreted intact after passing through the digestivetract. The rest is metabolized at the intestine mucosa and liverrendering detectable curcumin plasma levels (0.41–1.75 lM af-ter 1 h of oral dosing) when administered 4–8 g [126–128]. Ithas been shown that curcumin absorption is greatly improvedby the concurrent oral administration of piperine from blackpepper [128]. In light of these observations, currently greatefforts are being made to improve curcumin bioavailabilityand potentially study and exploit its therapeutic properties.This way novel curcumin formulations and complexes arebeing tested and include monocarbonyl analogs of curcumin[87], polymeric nanoparticle formulations of curcumin[92,129], and curcumin and phospholipids complexes [130]. Onthe other hand, curcumin administration has been shown tobe fairly safe for humans even at high doses of 12 g/day [131].Nevertheless, a recent study has pointed out the potential toxicactivity of several components of turmeric accompanying cur-cumin from an in silico analysis [132], what deserves furtherin vivo studies.

5. Conclusions

Curcumin is a highly pleiotropic and multiactivity moleculethat is capable of significantly affecting a wide variety of proc-esses, ranging from the catalytic activity of antioxidant andproinflammatory enzymes to the expression of multiple genesrelated to inflammation and redox biology. Curcumin is amicronutrient that is closely related to cellular redox balanceand thus to mitochondrial biology, making it the principal cellorganelle 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 affectthe mitochondria. Fat accumulation is a key process in manyliver 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 liverpathologies. Specific targeted therapies and/or agents for mito-chondrial disorders and related diseases or degenerative proc-

esses are extremely scarce, with many of them involvingsevere side effects [137]. On the other hand, despite the provenenormous therapeutic potential of curcumin and its safety forhuman use, it has not yet been approved for use in the treat-ment of any human disease. Therefore, future research intomitochondrial dysfunction-associated diseases, such as chronicliver disease, should focus on large, well-controlled humanstudies to fully develop the therapeutic potential of thismicronutrient.

AcknowledgementsL. Vera-Ramirez was supported by a postdoctoral contractfrom the Andalusian Regional government. P. P�erez-Lopez wassupported by a predoctoral FPI grant from the Spanish Minis-try of Science and Innovation. A. Varela-L�opez was supportedby a predoctoral FPU grant from the Spanish Ministry of Sci-ence and Innovation. The authors acknowledge the Universityof Granada and the Andalusian Regional government for sup-porting research of the group.

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