Lipids changes in liver cancer

Lipids changes in liver cancer 1 first-author †E-mail:jjtnew@163.com †E-mail:jjtnew@163.com jjtnew@163.com 2 1 1 Department of Tumor Biological Treatment, the Third Affiliated Hospital, Suzhou University, Changzhou 213003, China Department of Tumor Biological Treatment, the Third Affiliated Hospital, Suzhou University, Changzhou 213003, China Institute of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden Institute of Laboratory Medicine, Lund University, S-221 85 Lund, Sweden Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. Lipids Lipoprotein Liver cancer INTRODUCTION 1 The liver is a major organ in energy metabolism, and plays a critical role in the production metabolism of lipid and lipoprotein, regulating their synthesis and degradation (Tietge et al., 1998 1998 ); Liver function depends on the integrated activity of different hepatic cells and the injury of the organ could result in disintegrated intracellular functions (Sherlock, 1995 1995 ); Changed lipid and lipoprotein metabolism homeostatically is one of the foundations in various liver diseases, and is regulated by related substances (Lewis and Rader, 2005 2005 ). In addition, hepatic cells can draw help from lipoprotein receptor of the cells surface to absorb and clear lipoprotein metabolic products. Liver produced lipoprotein, as most of VLDL (very low density lipoprotein) and part of HDL (high density lipoprotein), and could keep opposite balanced state of lipid and lipoprotein metabolism by this way in vivo (Pangburn et al., 1981 1981 ). Most plasma proteins and endogenous lipoproteins were synthesized in liver (Levi, 1972 1972 ; Albers et al., 1977 1977 ), but the synthesis and secretion depended on the integrity of hepatocellular function (Eisenberg and Levy, 1975 1975 ), and is influenced by normal lipid and lipoprotein metabolism in liver diseases (Davis and Bryson, 1994 1994 ). Liver cancer was the fifth malignant tumor in the world (Parkin et al., 2001 2001 ), and was infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) which were common in China (Shi et al., 2005 2005 ), which is major remote cause of liver cancer (Nissen and Martin, 2002 2002 ; Guan et al., 2004 2004 ). The mortality of liver cancer was 20.4/100 000 in China, occupied 18.8% of all malignant tumors, and it was next to gastric cancer only. Compared to other countries in the world the mortality of liver cancer in China occupies the first place (Zhang et al., 1999 1999 ). The earlier period of liver cancer is often followed by hepatic cirrhosis process, so that liver function is damaged obviously by hepatic cirrhosis (Sherlock and Dooley, 1993 1993 ), and influences lipid normal metabolism in liver. Severe liver diseases could disorder lipoprotein metabolism and change lipid and lipoprotein level in serum (Cooper et al., 1996 1996 ; Motta et al., 2001 2001 ; Ooi et al., 2005 2005 ). In this article we specially discuss the changes of lipid and lipoprotein and the clinical significances in liver cancer. INFLUENCE OF LIVER CANCER ON TG METABOLISM 1 Patients with liver cancer are often followed by liver diseases. Liver cancer and chronic liver disease influence blood fat level (Cicognani et al., 1997 1997 ). Motta et al.( 2001 2001 ) detected that triglyceride (TG) level decreased 28.8% in 40 cases with liver cancer, and the reduction of TG levels observed in their study series may be explained on the basis of the relationship between cytokines and lipids (Malaguarnera et al., 1994 1994 ). Lipid metabolism products such as Tnf-α, IL-1, IL-6, and IFN-α are produced by tumor cells (Langstein and Norton, 1991 1991 ; Tracey et al., 1988 1988 ). In fact cytokines inhibited lipolysis (Gifford and Lohmann-Matthes, 1987 1987 ). Hepatic cells are damaged simultaneously in hepatocarcinogenesis, and in patients with this pattern, hepatic TG lipase activity significantly decreases (Hiraoka et al., 1993 1993 ). The X protein of hepatitis B virus (HBx) plays a major role in hepatocellular carcinoma. Apolipoprotein B (apoB) in the liver is an important glycoprotein for transport of VLDL and low density lipoproteins (LDL). In liver cells hyper-express of HBx causes negative accommodation of microsome TG transfer protein, could increase the expression of β-d-mannoside-1, 4-N-acetylglucosaminyl transferase-III (GnT-III), and causes inhibition of apoB secretion and accumulation of intracellular TG and cholesterol (Tch) (Kang et al., 2004 2004 ), but serum TG level in liver cancer did not obviously decrease compared with lipoprotein(a) (Lp(a)), Tch and HDL (Ooi et al., 2005 2005 ). INFLUENCE OF LIVER CANCER ON CHOLESTEROL METABOLISM 1 Cholesterol metabolism is a normal regulation process which first transformed choloic acid and desoxycholic acid through biliary system in liver, then as bile salt was passed to bowels through biliary system (Rothblat and Phillips, 1986 1986 ). When hepatic inadequacy occurred because of liver cancer and chronic liver disease, form, esterification and evacuation of cholesterol were blocked, which causes changes of plasma cholesterol level (Cooper et al., 1996 1996 ; Motta et al., 2001 2001 ; Ooi et al., 2005 2005 ; Heeren et al., 2004 2004 ; Kanel et al., 1983 1983 ; Popescu et al., 2003 2003 ); and it was also discovered that serum cholesterol level was negative correlated with occurrence and mortality of some cancers by epidemiologic study (Law and Thompson, 1991 1991 ; Williams et al., 1981 1981 ). Study of the correlation between total serum cholesterol and tumor showed that the cholesterol level in patients who died of cancer was significantly lower than that in those who survived (Cambien et al., 1980 1980 ). Liver cancer is a wasting disease, and with patient’s condition process, tumor cells proliferated and needed to intake large amount of cholesterol as raw material for cytomembrane synthesis (Funahashi et al., 1989 1989 ). Tumor cells cholesterol intake, synthesis and changes of membrane content suggested that endogenous cholesterol may play an important role in tumor pathobiology (Dessì et al., 1994 1994 ), and cholesterol metabolic products participated in duplication of DNA and regulation of oncogene protein (Casey et al., 1989 1989 ). Eighty percentage of endogenous cholesterol in serum is synthesized in liver cell cytomicrosome (Krisans, 1996 1996 ), since there are cholesterol synzymes in cytomicrosome (Grünler et al., 1995 1995 ). Developing from chronic hepatitis to liver cirrhosis resulted in reduced hepatic cell fibrosis and hydroxy-methyl-glutaryl coenzyme A (HMGCoA) reducase synthesis. With patient’s condition aggravating, cholesterol synthesis in liver reduced and serum cholesterol content gradually depressed, especially in liver cancer, which explained that serum cholesterol content depressed significantly when patient’s condition aggravated and liver function lesion intensified (Ooi et al., 2005 2005 ; Cooper et al., 1996 1996 ). Protein kinase C (PKC) is hypso-expressed in liver cancer, also is the major molecule in cell signal transduction pathway, and plays an important role in cell growth and aggravation (Carter, 2000 2000 ). In cancerization of liver cells the abnormality of cell signal transduction plays a key role, and the abnormal expression of PKC-α is closely correlated with genesis and development of liver cancer (Tu et al., 2001 2001 ; Perletti et al., 1996 1996 ). HDL receptor-mediated translocation and efflux of intracellular cholesterol occur through activation of PKC (Mendez et al., 1991 1991 ), while activation of PKC enhances and inhibition of PKC suppresses apolipoprotein-mediated cholesterol efflux (Mendez et al., 1991 1991 ). HDL causes serum cholesterol level to significantly decrease in liver cancer (Motta et al., 2001 2001 ). CHANGE OF LIPOPROTEIN IN LIVER CANCER 1 Liver is a major source of the endogenous lipoproteins in vivo, meanwhile, and it is the main site of the synthesis, storage, transport and degradation of lipid (Lewis and Rader, 2005 2005 ). Each protein is influenced by liver disease in a different way and serum lipoprotein concentrations with faster turn-over are more reduced with respect to those with slower turn-over (Phillips, 1960 1960 ). Metabolism of Lp(a) in liver cancer 2 The liver is the main site of Lp(a) synthesis (Malaguarnera et al., 1994 1994 ; 1996 1996 ; Kraft et al., 1989 1989 ). In the view of healthy controls, Lp(a) level in liver cancer patients’ serum strikingly decreased compared with that of the normal (Samonakis et al., 2004 2004 ), and it was found Lp(a) level decreased in liver cancer and cirrhotic patients. Lp(a) is produced by the liver and it is expected that its levels may decrease in patients with chronic liver disease (Samonakis et al., 2004 2004 ). That liver plays an important role in lipid metabolism and so it is quite certain that a malfunction of liver cells might influence serum Lp(a) levels. Several factors such as hormones, cytokines, genetics and nutrition may be involved in different way, with each single protein being synthetized by the liver (Phillips, 1960 1960 ). Several inflammatory and tumoral diseases are characterized by the production and delivery of cytokines influencing serum Lp(a) levels (Higuchi et al., 1988 1988 ), so serum Lp(a) is significantly lower in patients with liver cancer (Samonakis et al., 2004 2004 ). The mechanisms by which the tumours induce cachexia involve inflammatory cytokine production, which is responsible for a wide number of metabolic disorders, essentially involving lipid metabolism (Langstein and Norton, 1991 1991 ). Serum Lp(a) level changes during inflammatory disease (Maeda et al., 1989 1989 ); and also liver damage is linked to reduced Lp(a) serum levels (Malaguarnera et al., 1996 1996 ; Kostner, 1983 1983 ). Geiss et al.( 1996 1996 ) longitudinally observed patients showing a marked increase in Lp(a) concentration from 7 mg/dl in acute stage to 32 mg/dl in convalescence, and acute hepatitis is associated with decreased Lp(a) serum levels. Obvious Lp(a) half-life is brief in vivo (3.3~3.9 d) (Krempler et al., 1983 1983 ), and influenced early by liver function alterations (Malaguarnera et al., 1994 1994 ). Then Lp(a) is synthesized and metabolized independently of other plasma lipoproteins, at the same time the serum Lp(a) level is not influenced by various dietary manipulations (Albers et al., 1977 1977 ). Thus, Lp(a) is a substance involved in lipid and proteic metabolism, and can be a sensitive and early marker of liver malfunction. It is concluded that Lp(a) might be useful in the follow-up of liver cancer patients and that ferritin and α-fetoprotein can be used for a more complete evaluation of the liver function (Motta et al., 2001 2001 ), for analyzing the Lp(a) level in vivo, and for evaluating the liver functional status of hepatoma patients (Malaguarnera et al., 1996 1996 ; Motta et al., 2001 2001 ; Samonakis et al., 2004 2004 ), but the increased Lp(a) serum level was found in hepatoma patients (Basili et al., 1997 1997 ). Metabolism of HDL and LDL in liver cancer 2 HDL comprises a heterogeneous mixture of spherical macromolecules which differ in size (80~120 Å) and chemical composition; the main structural proteins are apoA-I (apolipoprotein A-I) and apoA-II (apolipoprotein A-II) (Assmann and Schriewer, 1980 1980 ). The apoA-I is present on most HDL particles and constitutes 70% of the apolipoprotein content of HDL particles; it is not only the structural protein of HDL, but also the activator of lecithin cholesterol acyl transferase (LCAT) (Lewis and Rader, 2005 2005 ), and most HDL particles contain apoA-I (Katsuramaki et al., 2002 2002 ). Differences in the quantitative and qualitative content of lipids, apolipoproteins, enzymes, and lipid transfer proteins result in the presence of various HDL subclasses, which are characterized by differences in shape, density, size, charge and antigenicity (von Eckardstein et al., 1994 1994 ). Reverse cholesterol transport (RCT) is a pathway transporting cholesterol from extrahepatic cells and tissues to the liver, which antiport process is determined at least partially by the HDL concentration in the blood (Sviridov and Nestel, 2002 2002 ); HDL plays an important role in cleaning the cholesterol (Fielding and Fielding, 1995 1995 ). Cholesterol ester transfer protein (CETP) is an important determinant of lipoprotein function, especially HDL metabolism, and contributes to the regulation of plasma HDL levels (Hirano et al., 2001 2001 ). Therefore, HDL plays a key role in the reverse cholesterol transport pathway in liver (Sviridov et al., 1997 1997 ; Genest et al., 1990 1990 ). But when cells are incubated with equivalent concentrations of isolated lipoproteins, HDL is much more effective in promoting 14C cholesterol efflux than LDL, suggesting that unesterified cholesterol is initially transferred to HDL and then to LDL (Sviridov and Fidge, 1995 1995 ), indicating that the primary site of human HDL synthesis is putatively in the liver (Eggerman et al., 1991 1991 ; Garcia et al., 1996 1996 ). In earlier period of liver cancer it often follows hepatic cirrhosis process, so that liver function is damaged obviously by hepatic cirrhosis (Sherlock and Dooley, 1993 1993 ). Ooi et al.( 2005 2005 ) analyzed lipids in liver diseases by agarose gel electrophoresis, and differential staining and simultaneous analysis of the lipid and lipoprotein fractions, including chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and metastatic liver cancer, with each fraction being compared among these diseases. Metastatic liver cancer showed lower HDL-fraction level, but higher levels of the other parameters than HCC. When the subjects were classified into survivors and patients who died, the HDL fraction level in HCC and metastatic liver cancer, and the LDL level in LC and metastatic liver cancer differed between survivors and patients who died, with atypical patterns being frequently observed in patients who died. There were 6 atypical patterns, of which 4 (slow α-HDL, abnormal LDL, Lp-X (lipoprotein X) and Lp-Y (lipoprotein Y)) were associated with liver diseases. Slow alpha HDL appeared during slight bile stagnation and was accompanied by increases in the apoE (apolipoprotein E) level and the HDL particle size. The LDL level in LC and metastatic liver cancer differed between survivors and patients who died, also the function of the entire liver decreases in LC while HCC develops in the LC stage in patients. To establish whether there is any significant relationship between high density lipoprotein cholesterol (HDLC) concentrations and biopsy-documented liver disease, Kanel et al.( 1983 1983 ) reported that 169 patients had needle biopsies, serum cholesterol and HDLC evaluated. HDLC decreased strikingly and significantly in acute alcoholic hepatitis and in acute viral hepatitis; compared to controls, patients with inactive alcoholic liver disease and chronic active hepatitis showed moderate decrease in HDLC, and patients with primary and metastatic hepatic neoplasms also had strikingly decreased HDLC (Booth et al., 1991 1991 ). The patient’s condition proceeded, developed and changed, it caused HDL physiology function to change (Motta et al., 2001 2001 ; Kanel et al., 1983 1983 ; Montaguti et al., 1975 1975 ; Rubies-Prat et al., 1983 1983 ; Skipski et al., 1975 1975 ). Hepatic lipase can adversely affect the HDL2 selectively, hydrolyze the TG and lipoprotein in it (Dugi et al., 1997 1997 ). After lipoprotein of HDL2 is hydrolyzed, the cholesterol/phospholipid (C/PC) ratio on the surface increased, promoted cholesterol and its lipid flowing into hepatic cell, which is favourable for liver to uptake HDL2 cholesterol and lipid to synthesize bile acid. At the same time, HDL2 is changed into HDL3 and enters the blood circulation. Liver can take cholesterol and its lipid from tissue outside of liver. This process plays an important role in the antiport of cholesterol, and the phospholipase A1 activity of hepatic triglyceride lipase (H-TGL) in stimulating the delivery of HDL esterified cholesterol into liver cells (Marques-Vidal et al., 1994 1994 ). Hepatic lipase (HL) mediates increase in selective uptake of HDL-associated cholesteryl esters (Rinninger et al., 1998 1998 ), and stimulates the internalisation of apoB-containing lipoproteins by hepatocytes independent from lipolysis. The HDL role in the hepatic metabolism of apoA-I-containing lipoproteins, i.e. HDL was investigated, which explored the role of these molecules in the HL effect on selective cholesterol esters uptake. Hepatoma cells were depleted of proteoglycans or Chinese hamster ovary (CHO) cells deficient in proteoglycan synthesis were used. Proteoglycan-deficiency reduced the HL-mediated increase in selective uptake by more than 80% (Rinninger et al., 1998 1998 ), and caused the inverse correlation between HL activity and HDLC (Dugi et al., 2001 2001 ), so that hepatic lipase stimulates the uptake of HDLC by hepatoma cells (Bamberger et al., 1983 1983 ). Hepatoma cells exposed to hepatic lipase-modified HDL, showed increased uptake of HDL free cholesterol relative to cells exposed to control HDL, and resulted in the decrease of HDLC level in vitro (Kanel et al., 1983 1983 ). It was confirmed that transgenic overexpression of HL in either mice or rabbits decreased HDLC levels (Busch et al., 1994 1994 ; Santamarina-Fojo et al., 1998 1998 ). HL activity is suppressed by estradiol and increased by testosterone (Brinton, 1996 1996 ; Tan et al., 1998 1998 ), and when patients’ estradiol level with HCC was high, the secreting ability of testosterone will be cut down, which decreases HDLC level too. Experiment in vitro showed the capacity for cellular cholesterol efflux from HUH-7 cells is slightly impaired by acute-phase (AP)-HDL. Compared with HDL, it is supportive of scavenger receptor class B, type I (SR-BI). Hepatic tissue can modulate its recognition of HDL. The human hepatoma cell line, increases HDL binding with cholesterol loading that is specific for HDL3, and hepatic membranes from a patient lacking normal hepatic LDL receptors bound apoA-I HDL normally, indicating that a saturable, specific regulatable receptor for apoE-free HDL is present in human liver, and that there is a free HDL apoE which can be saturated and regulated specially in humen liver (Hoeg et al., 1985 1985 ). INFLUENCE OF LIVER CANCER ON APOLIPOPROTEINS 1 Serum concentrations of apoA-I and apoA-II were determined in liver cancer, and the HDL fraction and apoA-I and apoA-II showed significantly low values (Hachem et al., 1986 1986 ). The liver participated in the reaction converting proapoA-I to the mature apoA-I; and also the proportion of proapoA-I showed a tendency toward increase with advance in liver damage (Matsuura et al., 1988 1988 ). With the short half-life, changes of the serum apoA-I levels may be a good indicator of the hepatic protein synthesis ability during the perioperative period after hepatectomy (Krempler et al., 1980 1980 ; Katsuramaki et al., 2002 2002 ). It also serves as an excellent parameter for predicting liver function after orthotopic liver transplantation (Tietge et al., 1998 1998 ; Malmendier et al., 1992 1992 ). The uptake and composition of cholesterol increased to satisfy the requirement of proliferation in malignant tumor cells which obviously increases cholesterol in its membrane. And the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to reduce the rate-limiting enzyme of cholesterol composition has increased. Lipids or proteins of α-HDL are removed from the circulation by at least 2 direct pathways involving the selective uptake of lipids by scavenger receptor B and the holoparticle uptake by apoE or apoA-I receptors (Curtiss and Boisvert, 2000 2000 ; Krieger, 1999 1999 ; Tall et al., 2000 2000 ; Trigatti et al., 2000 2000 ). Silver et al.( 2000 2000 ) suggested the presence of a hepatic leptin-regulated HDL receptor, which regulates HDLC levels by mediating holoparticle uptake into liver cells, after internalization of triglyceride-rich lipoproteins (TRL) in hepatoma cells, TRL particles are immediately disintegrated in the early endosomal compartment. This involves the targeting of lipids and apoB along the degradative pathway and the recycling of TRL-derived apoE through recycling endosomes (Heeren et al., 2004 2004 ). Lipoprotein metabolism is determined by the importance of hepatic apoE, and expression level determines the fate of LDL and HDL3 (Charpentier et al., 2000 2000 ). Slow α-HDL appeared during slight bile stagnation and was accompanied by increases in the apoE level and the HDL particle size with liver cancer (Ooi et al., 2005 2005 ). The redistribution of apoE from HDL to apoB-containing lipoproteins upon activated lipogenesis in hepatoma cells occurs intracellularly and is not attributable to decrease in HDL production (Fazio and Yao, 1995 1995 ), although studies in recombinant cells indicated that SR-BI can promote cholesterol efflux (Mulcahy et al., 2004 2004 ). Investigations of transgenic mice overexpressing or deficient in SR-BI indicate its physiological function as selectively sequestering cholesteryl esters from HDLs (Artl et al., 2002 2002 ), which result in plasma HDLs being cleared from the circulation by specific receptors, and being either totally degraded or their cholesteryl esters being selectively delivered to cells by receptors such as the SR-BI, which suggested that apoC-II and apoC-III inhibit selective uptake of low- and high-density lipoprotein cholesteryl esters in HepG cells (Huard et al., 2005 2005 ). INFLUENCE OF LIVER CANCER ON FATTY ACID METABOLISM 1 The liver is a critical organ in fatty acids of metabolism (Cowen and Campbell, 1977 1977 ). Fatty acid is also the source of liver triacylglycerol (Donnelly et al., 2005 2005 ). The extracellular free fatty acids (FFA) pool in tumors undergoes continuous turn-over, probably utilizing adipose tissue deposits as a source (Mermier and Baker, 1974 1974 ), and plasma FFA are increased in tumor bearing animals (Frederick and Begg, 1956 1956 ). Available evidence (Ockner et al., 1993 1993 ) is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this process, which in turn leads to alterations in gene expression and in DNA itself. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues. FFA concentrates in the serum of mice with mammary tumors. Similar results have been reported by various authors (Iguchi et al., 1989 1989 ; Kumar et al., 1991 1991 ; Lin et al., 1992 1992 ). Bravo et al.( 1990 1990 ) found increased unsaturated FFA concentrations in transplantable Friend leukemic cell tumors, and someone believed that they represented a metabolic and energy substrate for the tumor itself (Spector, 1967 1967 ). Morris hepatoma 7777 cells freshly isolated from highly malignant tumors grown in the hindlimb of buffalo rats actively convert ketone bodies to cholesterol and fatty acids. The results are discussed in terms of the known and proposed metabolic pathways for lipid synthesis from ketone bodies, particularly that from 3-hydroxybutyrate (Hildebrandt et al., 1995 1995 ). Hanai et al.( 1993 1993 ) evaluated 17 hepatectomized cases (12 cases of hepatocellular carcinoma and 5 cases of metastatic liver cancer). The cancerous tissues and the noncancerous reference tissues were separated, and the fatty acids were determined as methyl esters by gas chromatography. In HCC, the levels of α-linolenic acid (omega-3) and docosahexaenoic acid in liver cancer tissue were significantly less than those in the reference tissues, and eicosanoid production and the compositions of precursor fatty acids were determined in human cancerous and reference liver tissues. But the FFA in ascitic fluid improves diagnosis in malignant abdominal tumors (Greco et al., 1995 1995 ). The elevation of FFA in ascitic fluid allows discrimination between malignant and non-malignant ascites. The fasting concentration of FFA in the ascitic fluid was determined in 14 patients with malignant ascites and in 19 patients with liver cirrhosis. In malignant ascites FFA levels were increased more than three times compared with that in cirrhotic ascites. Palmitic acid was the most representative saturated FFA, while unsaturated FFA were represented, in decreasing order, by oleie, linoleic and arachidonic acids. The ratio of unsaturated to saturated FFA was higher in neoplastic patients. Available evidence (Ockner et al., 1993 1993 ) is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this process, nonneoplastic liver injury, and tumorigenesis in other tissues. de Alaniz and Marra ( 1994 1994 ) also demonstrated significant contribution of the stearoyl-CoA desaturase system to the high levels of oleic acid present in this kind of hepatoma cells. Peroxisome proliferators comprise a diverse group of chemicals which are regarded as rodent hepatocarcinogens and/or liver tumor promoters (Palut, 1997 1997 ). Cyclooxygenase-2 (COX-2) is an isoform of cyclooxygenase, which is the key enzyme converted arachidonic acids to prostaglandins. Hu ( 2003 2003 ) evaluated that COX-2-prostanoid pathway plays important and complex roles in the pathogenesis of various liver diseases and provides the rationale for further testing COX-2 inhibitors as clinical agents for HCC chemoprovention. Kondo et al.( 1999 1999 ) reported increased levels of COX-2 in hepatocellular carcinoma, examined the expression of COX-2 protein by immunohistochemistry in 53 patients with HCC, and found 17% of samples showing a high COX-2 expression, and 37% of samples expressed COX-2 at a moderate level. Cyclooxygenase (COX) is a key enzyme in the synthesis of prostanoids. Koga et al.( 1999 1999 ) investigated the expression of COX-2 and COX-1 in human HCC tissues using the above-mentioned methods to show high expression of COX-2 in well-differentiated HCC and low expression in advanced HCC, in contrast to its continuous expression during colorectal carcinogenesis, which suggested that COX-2 may play a role in the early stages of hepatocarcinogenesis. Shiota et al.( 1999 1999 ) studied twenty-eight of 29 (97%) patients with HCC showing a positive staining and immunohistochemically examined expression of this enzyme in cancerous and non-cancerous tissues of HCC. COX2-prostanoid pathway may also be involved in malignant invasion during hepatocarcinogenesis (Bae et al., 2002 2002 ). Keler et al.( 1992 1992 ) showed that dietary linoleic acid increases hepatoma growth. Fish oil was found to inhibit hepatic carcinogenesis (Ramesh and Das, 1995 1995 ) and decrease growth (Fox and Hay, 1992 1992 ). It is probable that this effect of linoleic acid is mediated through prostaglandin E2 (PGE2). Portal PGE2 had also been shown to suppress liver-associated immunity, and promote the formation of hepatic metastases (Okuno et al., 1995 1995 ). Albumin carries fatty acids and is suggested to act as an antioxidant; polyunsaturated fatty acids (linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids) inhibit growth of human hepatoma cells at low albumin concentration (0.5%) (Hostmark and Lystad, 1992 1992 ). Ramesh and Das ( 1995 1995 ) studied a diethylnitrosamine (DEN) induced hepatoma model, the effect of fish oil, a rich source of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), ground nut oil, oleic acid (OA) and linoleic acid (LA), and found that a ‘high fat’ diet and lipid peroxidation can modulate DEN-induced hepatocarcinogenesis in rats. The metabolism of arachidonic acid (AA), EPA, and DHA was examined in HepG2 cells, with the results suggesting that the levels of AA and DHA in both types of cells were regulated more severely than EPA and that the activity of fatty acid desaturation might be different between n-6 and n-3 families (Fujiyama-Fujiwara et al., 1992 1992 ). Polyunsaturated fatty acids killed incubated human tumor cells (Bégin et al., 1985 1985 ), suggesting that treatment of malignancy with polyunsaturated fatty acids may have considerable potential while being associated with a high level of safety. The effects of essential fatty acids on cell proliferation and cell viability of 3 human tumor and 4 normal cell lines were tested in vitro; the treatment of cancer with polyunsaturated fatty acids containing 3, 4, and 5 double bonds has potential clinical usefulness (Bégin et al., 1986 1986 ). CONCLUSION 1 It is thus evident that the liver plays a vital role in the production and clearance of a large number of lipoproteins, and is an important determinant of the plasma levels of various lipids (Cooper et al., 1996 1996 ) which were analyzed in liver diseases, showed results reflecting the pathologic conditions, and may be clinically useful (Ooi et al., 2005 2005 ); and also it may be a good indicator of the hepatic protein synthetic ability during the perioperative period after hepatectomy (Katsuramaki et al., 2002 2002 ). Drinking instant coffee powder results in amelioration of abnormal lipoprotein profiles that occurred in hepatoma-bearing rats, and instant coffee powder has the ability to suppress tumor cell invasion by reducing oxidative stresses in vitro, leading to the inhibition of tumor growth and metastases (Miura et al., 2004 2004 ). 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Mortality of primary liver cancer in China from 1990 through 1992 10.1631/jzus.2007.B0398 Project (No. 30570752) supported by the National Natural Science Foundation of China 2006-07-31 2007-01-23 2022-01-05 Copyright © 2007, Journal of Zhejiang University Science 2007 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 06 08