The patients with HCC frequently have other liver diseases such as chronic hepatitis and cirrhosis. All these conditions (hepatitis and cirrhosis of the liver) are often associated with plasma lipid and lipoprotein aberrations 25. It has been demonstrated that plasma triglycerides (TG) decreased by 20–30% in the patients with HCC 21. In contrast, Alsabti 26 reported that serum TG in HCC patients were increased when compared to those with cirrhosis. Ooi, et al., 22 reported that plasma TG levels in HCC patients were not significantly different compared with controls. These results emphasize the fact that changes of plasma lipid profile may not always imply the presence of HCC and one need to exercise caution in interpreting these results.

It is known that lipids and lipoprotein metabolism could be regulated by cytokines. For instance, interleukin-6 (IL-6), tumor necrosis factor (TNF-α), IL-1 may inhibit TG synthesis 27. Tumor cells are known to produce large amounts of pro-inflammatory cytokines that, in turn, may suppress plasma TG levels. Argiles, et al., reported that IL-1 profoundly affects lipid metabolism by delaying intestinal absorption and decreasing tissue uptake 28. IL-2 could induce severe hypocholesterolemia that is mediated by the inhibition of lecithin:cholesteryl acyltransferase (LCAT) activity 29. IL-1 and IL-6 significantly decreased microsomal triglyceride transfer protein (MTP) mRNA levels in HepG2 cells 30. It is believed that MTP is related to the synthesis of very low density lipoprotein (VLDL) 31. In addition, these cytokines could also decrease lipolysis in vivo 32. Similar results have been reported in other types of cancers 33.

About 80% endogenous cholesterol are synthesized in the hepatocellular microsomes that contain cholesterol synthesis enzymes 3435. In HCC and chronic liver diseases the synthesis and metabolism of cholesterol are impaired. It leads to a decrease in plasma cholesterol levels 19212236. Li reported 37, in a forward investigation, the relationship between serum cholesterol and occurrence of cancers in 9021 employees aged from 35 to 64 years old. No evidence of association of serum cholesterol level with total cancer mortality was seen by Log-rank trend test. But there was a significant negative correlation between serum cholesterol level and HCC (P < 0.05). This negative correlation also existed between serum cholesterol level and chronic hepatitis and liver cirrhosis. Similar results were described in patients with gastrointestinal cancer, however, lower cholesterol levels are not related to the cancer stages 38. Decreased serum cholesterol concentrations were also found in other cancers 394041, which are probably related to the increased consumption of cholesterol by the tumor cells, as cholesterol levels in the hepatoma tissues were doubled compared to the control tissues 42. In addition, it has been reported that synthesis of cholesterol is reduced under cancers 43, and moderate increases of serum cholesterol levels and increased body mass index (BMI) may have a protective effect on cancer mortality 4445. It was observed that the plasma HDL-cholesterol was inversely correlated to the cholesterol levels in the tumor tissues in cancer patients 46. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it is possible to hypothesize that lower HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in these proliferating tissues 46.

Liver is a key organ for the metabolism of free fatty acids (FFA) 47, and FFA are the source of TG synthesis in the liver 48. The extracellular FFA pool in tumors undergoes continuous turnover, utilizing adipose tissue storage as a source 49. It is reported that plasma FFA are increased in tumor bearing animals 50. Increased plasma FFA is attributed to the hypermetabolic state in cancers 51. Li, et al., 52 reported that proportions of plasma saturated and monounsaturated fatty acids in the HCC patients were significantly increased compared to the controls. Similar results were found in the patients with breast cancer suggesting that this could be a common finding in tumors 53. It is believed that these FFA could be used as metabolic substrates by the tumor cells 54. Hanai, et al. 55 evaluated seventeen hepatectomized cases (12 cases of HCC and 5 cases of metastatic liver cancer). In HCC tissues, the levels of alpha-linolenic acid (LA) and docosahexaenoic acid (DHA) were significantly less than those in the reference tissues those normal tissues surrounding tumors. Wood, et al., 56 analyzed total lipid extracts of liver tissue from 14 HCC patients and demonstrated that ratio of saturate C18 to unsaturated C18 in the tumor tissues were significantly and consistently lower than those corresponding non-tumor tissues. Palmitic acid was the most representative saturated FFA, while unsaturated FFA was represent, in decreasing order, by oleic, linoleic and arachidonic acids (AA) 57. Available evidence 58 is consistent with the possibility that selective changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to the activity of the extramitochondrial pathways, which may also contribute to liver injury and tumorigenesis. De Alaniz and Marra 59 demonstrated a significant contribution of the stearoyl-CoA desaturase system to the high levels of oleic acid (OA) present in hepatoma cells. Peroxisome proliferators are diverse group of chemicals which are regarded as rodent hepatocarcinogens and/or liver tumor promoters 60. It has been demonstrated that peroxisome proliferators could increase hepatocyte proliferation and cause liver tumors in rodents, which is related to transcriptional activation of peroxisome proliferators-activated receptor (PPAR)-α regulated genes and the resulting excessive generation of H₂O₂. Evidence from mice lacking fatty acyl-CoA oxidase (AOX), PPAR-α and PPAR-α/AOX has confirmed the role of PPAR-α in the development of HCC 616263. As PPAR-γ functions as a regulator of cell survival and growth in the HCC, PPAR-γ therefore represents a putative molecular target for chemopreventive therapy or inhibition of HCC growth 64. In addition, decreased expression of hepatic PPAR-α functions as one mechanism underlying the pathogenesis of HCV infection, PPAR-α may serve as a new therapeutic target in traditional treatment of HCV-induced liver injury 65.

Liver represents the main site of lipoprotein (a) (Lp(a)) synthesis 666768. Half-life of Lp(a) is about 3.3–3.9 days in human plasma 69, which is influenced in the early stage when liver function was impaired 66. Lp(a) is synthesized and metabolized independently of other plasma lipoproteins, and Lp(a) level is not influenced by various dietary manipulations 70. Motta, et al., 21 demonstrated that Lp(a) levels were significantly lower in the HCC patients (5.7 ± 2.08 mg/dl) than in the controls (16.78 ± 16.24 mg/dl). Higuchi, et al., 71 elucidated that influences of serum Lp(a) levels in some tumors could be characterized by the production and deliverance of cytokines. It has been reported that serum Lp(a) were significantly lower in the HCC patients 7273. However, Geiss, et al., 74 observed patients with acute hepatitis showed a marked increase in Lp(a) concentration, i.e., 7 mg/dL in acute stage and 32 mg/dL in the convalescence of the disease. Basili, et al., reported that Lp(a) could also be increased in the patients suffered from HCC together with cirrhosis 75. It has been demonstrated that Lp(a) together with ferritin and alpha-fetoprotein could be a sensitive and early marker to evaluate liver function 21. As Lp(a) has positive correlation with the hepatic status, it has been suggested that Lp(a) could be considered as a index of liver function 216876.

The origin and fate of HDL are less well understood than other lipoproteins. HDL may be formed both in the intestine and in the liver. During lipolysis of TG-rich lipoproteins, HDL particles are also formed. ApoAI and apoAII are the major apolipoproteins of the HDL. Production rate of apoA-I is an important determinant of the variability of plasma HDL concentrations. It is influenced by many factors and apoA-I transcriptional regulation has an impact on plasma HDL concentrations. Nutritional interventions such as, a switch from high-carbohydrate to a high-fat diet appears to exert their major effect on the production rate of apoA-I rather than on clearance 2077. HDL plays a key role in the reverse cholesterol transport pathway (RCTP) 2478. It has been demonstrated that HDL fraction offers a new approach to study liver diseases 19. Ahaneku, et al., 36 analyzed HDL-fraction levels including HDL-cholesterol (HDL-C), HDL-phospholipids (HDL-PL) and the ratio of HDL-C/HDL-PL, in HCC patients and compared with the controls. They found that plasma HDL-C, HDL-PL and HDL-C/HDL-PL were significantly lower in HCC patients than those in the controls. Motta, et al., 21 studied 40 patients with HCC, and evaluated the LDL-C, HDL-C. In patients with HCC, LDL-C level was significantly lower than in the controls, but HDL-C did not show a statistically significant difference to the controls. Kanel, et al., 79 reported that patients with primary or metastatic liver cancer had strikingly decreased HDL-C. Ooi, et al., 22 suggested that HDL-C may be clinically useful to reflect the pathologic conditions, and can be used to evaluate the severity of liver diseases. In the metastatic liver cancer showed a lower HDL-fraction level too, even lower than those in the HCC patients. Also, Fujii, et al., 23 found existence of HDL with an abnormal apoprotein composition or a more profound decrease of HDL3 than those of HDL2 in severe hepatocellular dysfunction of cholestasis. Cooper, et al., 19 observed that there was a rapid decreases of HDL-cholesterol and LDL-cholesterol immediately after hepatic resection. Lipid profiles are different in the cirrhosis patients with or without HCC. In cirrhosis with HCC plasma phospholipid levels showed a significant negative correlation with total bilirubin and alanine aminotransferase. Total cholesterol (TC), phospholipids (PL) and the ratio of TC/PL were elevated, while HDL-C, HDL-PL, HDL-C/TC and HDL-PL/PL were normal. It is suggested that variations in the level of plasma lipids and lipoproteins may assist in describing the nature of these two forms of liver disease 36.

Liver is the main organ for the synthesis, storage, transportation and degradation of some apolipoproteins 20. Each protein may be 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 80. Serum concentrations of apoAI and A-II were significantly lower in the patients suffered from HCC 2324, but an increase in the proportion of proapoAI was found in patients with HCC 81. The proportion of proapoAI showed a tendency toward increase under advanced liver damage because liver participates in the process of converting proapoAI to the mature apoAI. It is suggested that plasma apoAI could reflect the hepatocellular dysfunction 21982. The pattern of changes in the serum apoAI levels may be a good indicator of the hepatic protein synthetic ability during the perioperative period after hepatectomy 82. ApoB in the liver was an important glycoprotein for transportation of VLDL and LDL, in liver cells hyperexpression of HBx caused accommodation of MTG, HBx could increase the expression of beta-d-mannoside-,-N-acetylglucosaminyl transferase-III (GnT-III), and it could inhibit apoB secretion and enhanced the accumulation of intracellular triglyceride and cholesterol 83. Ooi et al., 22 reported that slow alpha HDL appeared in the metastatic liver cancer in the early-middle stages, during slight bile stagnation, and accompanied by increases of apo E levels 84. In our preliminary study we have observed that apolipoprotein M (apoM) mRNA levels were significantly lower in the HCC tissues than those in the normal hepatic tissues surrounding tumors (non-published data). Up to date there is no data reported concerning other apolipoproteins in relation to liver cancer.

HDL transports cholesterol to liver cells, where they are recognized and taken up via specific receptors. Cholesteryl esters within HDL are selectively uptaken by hepatocytes via the scavenger receptor class B type I (SR-BI). An interesting feature of SR-BI is that the receptor selectively translocates HDL-cholesteryl esters from the lipoprotein particle to the cytosol of the liver parenchymal cells without a parallel uptake of the apolipoproteins and this property may allow for the delivery of its loaded drugs avoiding lysosomal degradation 85. As HDL and LDL have high affinity and could be accumulated in tumor cells 868788, they have been used as carriers for delivery of anti-tumor drugs into hepatoma cells to treat HCC 858990919293. Masquelier, et al., 94 investigated the possibilities to use LDL as a drug carrier to increase the selectivity of anti-tumor drugs in cancer chemotherapy. It has been demonstrated that both HDL and LDL may be used as endogenous targeting carriers into tumor cells, which have high lipoprotein-receptor activities, in animal models 8895. Anti-cancer drug-HDL complexes work as efficient drug delivery vehicles due to the ability of cancer cells to acquire HDL core components 8996. Complex of anti-cancer drugs with HDL and LDL does not influence characteristics of the drugs 92. Lacko, et al., demonstrated that administration of anti-cancer drug-HDL complex may reduce toxic side-effects during the chemotherapy 89. Lou, et al., reported in a cell culture system that cellular uptake of recombinant HDL-aclacinomycin (ACM) by the SMMC-7721 hepatoma cells was significantly higher than that of free ACM at the concentration range of 0.5–10 μg/mL (P < 0.01). Cytotoxicity of recombinant HDL-ACM to SMMC-7721 cells was significantly higher than that of free ACM at concentration range of less than 5 μg/mL (P < 0.01) and IC50 of recombinant HDL-ACM was lower than IC50 of free ACM (1.68 nmol/L vs 3 nmol/L) 85. Chu, et al., coupled doxorubicin (DOX) to human LDL to form a LDL-DOX complex. When the complexes injected into mice, LDL-DOX was more accumulated in liver than free DOX. In contrast, LDL-DOX was less accumulated in heart than free DOX 97. It suggested that both HDL and LDL could be used as carriers to conjugate water-insoluble anti-cancer drugs leads to a higher accumulation of the drugs locally and specifically.