Metabolism of high density lipoproteins in liver cancer

Abstract

Liver plays a vital role in the production and catabolism of plasma lipoproteins. It depends on the integrity of cellular function of liver, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs these processes are impaired and high-density lipoproteins are changed.

Key Words: High density lipoproteins, Metabolism, Liver cancer

INTRODUCTION

Liver cancer is often followed procession of chronic hepatitis or cirrhosis, therefore hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo[1,2]. In this review we summarized the high density lipoproteins (HDL) metabolism in liver cancer.

Biologic character and physiological functions of HDL

HDL are a heterogeneous mixture of spherical macromolecules which differ in size (80-120A), and chemical composition (apolipoprotein A-I, apolipoprotein A-II)[3]. ApoA-Iis present on the majority of HDL particles and constitutes 70% of the apolipoprotein content of HDL particles[4], It is involved in the metabolic interconversions that occur as a result of cholesteryl ester transfer protein (CETP), lecithin: cholesterol acyltransferase (LCAT) and lipase activities and their role in the formation of mature HDL and in reverse cholesterol transport[5]. And Kunitake et al[6] reported that the pre-beta sub-population can be observed directly in fresh plasma by immunoelectrophoresis. It contains phospholipid and free and esterified cholesterol. But, protein constitutes 90% of its mass, and the protein moiety of this subpopulation exhibits markedly lower helicity than that of high density lipoproteins isolated by ultracentrifugation. It was utilized gelose gradient polyacrylamide gel and divided α-HDL to HDL_2a, HDL_2b and HDL₃[7], also in association with a few molecules of sphingomyelin and phosphatidylcholine, β-HDL was divided β₁-, pre β₂- and pre β₃-HDL[8-11].

The majority of the HDL particles contain apoA-I. 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[7]. It is accepted that a low level of HDL cholesterol is an important cardiovascular risk factor[12]. Also, the liver is a major source of the plasma lipoproteins[4]. These data indicate that the putative primary site of human HDL synthesis is in the liver[13,14]. Epidemiological studies have shown that obesity is a risk factor for hepatocellular carcinoma[15].

Metabolism of HDL in liver

It is a relative balance in metabolism of cholesterol and lipoprotein under normal liver function, it was influence of metabolism in lipoprotein with liver disease[16], and an impaired lipid metabolism is often found in patients with chronic liver diseases[17]. HL activity is suppressed by estradiol and increased by testosterone[18,19], estradiol to advance in liver cancer, but testicular hormone secrete ability is depressed, it was confirmed that transgenic overexpression of HL in either mice or rabbits decreased HDL-C levels[20,21].

In addition, in the hepatocellular metabolism of long-chain fatty acids suggest that increased fatty acid oxidation by way of extra mitochondrial pathways results in a corresponding increase in the generation of hydrogen peroxide, thus, oxidative stress leads to alterations in gene expression and in DNA itself, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues[22]. As a result of lipid peroxidation probably play significant roles in clonal expansion and hepatocellular carcinoma progression[15]. Liver cancer is frequent malignant tumor, most of them based liver cirrhosis, and hepatic function was damaged obviously, analysis of the cholesterol (Chol) and triglyceride (TG) fractions. Liver diseases were classified into chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and metastatic liver cancer, and each fraction was compared among these diseases. Metastatic liver cancer showed a lower HDL-fraction level, but higher levels of the other parameters than HCC. 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. Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful[23].

Metabolism of reverse cholesterol transport of HDL in liver cancer

Reverse cholesterol transport (RCT) is a pathway transporting cholesterol from extrahepatic cells and tissues to the liver, and perhaps intestine, for excretion. That antiport process is determined at least partially by the HDL concentration in the blood[24], uptake of cholesterol from cells by specific acceptors, esterification of cholesterol within HDL by LCAT transfer of cholesterol to the apoB-containing lipoproteins (cholesterol transfer); remodeling of HDL and uptake of HDL cholesterol by the liver and possibly also by kidney and small intestine through lipoprotein receptors[9]. CETP is an important determinant of lipoprotein function, especially high density lipoprotein metabolism, and contributes to the regulation of plasma HDL levels[25]. So high density lipoprotein plays a key role in the reverse cholesterol transport pathway in liver[26,27].

The liver contributes free cholesterol to the plasma lipoproteins which participate in the process of reverse-cholesterol transport. But when cells were incubated with equivalent concentrations of isolated lipoproteins, HDL was much more effective in promoting [14C] cholesterol efflux than LDL, suggesting that unesterified cholesterol is initially transferred to HDL and then to LDL[28]. Serum concentrations of apolipoprotein A-Iand A-II were determined in patients with hepatic metastases of colorectal cancer, with primary liver cancer and with cirrhosis. In all three liver diseases, the HDL fraction and apolipoproteins A-Iand A-II showed significantly low values[29]. To establish whether there is any significant relationship between high-density lipoprotein cholesterol concentrations and biopsy-documented liver disease, 169 patients had needle biopsies, serum cholesterol, and HDLC evaluated. In both men and women, HDLC decreased strikingly and significantly in acute alcoholic hepatitis and in acute viral hepatitis, compared to controls. Men and women with inactive alcoholic liver disease and chronic active hepatitis showed moderate decreased in HDLC. Patients with primary and metastatic hepatic neoplasms also had strikingly decreased HDLC[30].

Cell surface receptor influence HDL metabolism in liver cancer

Hepatoma cell lines serve as a suitable model for the study of hepatic receptors for lipoprotein in man[31]. The experiments also demonstrate that the responses at least of some of the receptors of the hepatoma cells in culture resemble those of hepatocytes in vivo and in vitro[32].

The importance of hepatic apolipoprotein (apo) E in lipoprotein metabolism is evidenced by the fact that the level of apoE expression determines the fate of LDL and HDL3[33]. Although studies in recombinant cells indicate that scavenger receptor class B, typeI(SR-BI) can promote cholesterol efflux, investigations in transgenic mice overexpressing or deficient in SR-BI support its physiological function as selectively sequestering cholesteryl esters from high density lipoproteins[34].

Impaired capacity of acute-phase high density lipoprotein particles to deliver cholesteryl ester to the hepatoma cell line[35] suggest that plasma high-density lipoproteins are cleared from the circulation by specific receptors and are either totally degraded or their cholesteryl esters are selectively, delivered to cells by receptors such as the scavenger receptor class B typeI(SR-BI)[36]. The fact that the capacity for cellular cholesterol efflux from HUH-7 cells is slightly impaired by AP-HDL (compared with HDL) is supports the concept that scavenger receptor class B, typeI(SR-BI), of the human hepatoma cell line, increased HDL binding with cholesterol loading that was specific for HDL3, and hepatic tissue can modulate its recognition of HDL. Hepatic membranes from a patient lacking normal hepatic LDL receptors bound apo A-IHDL normally. These data indicate that a saturable, specific regulatable receptor for apo E-free HDL is present in human liver[37].

Lipids or proteins of α-HDL are removed from the circulation by at least 2 direct pathways, which involve the selective uptake of lipids by scavenger receptor B1 (SR-BI) and the holoparticle uptake by apoE or apoA-Ireceptors[38-41]. ApoE-containing HDLs, which constitute the minority of HDLs, are internalized by hepatic apoE receptors (LDL receptor and LDL receptor-related protein)[42]. Tall and colleagues have suggested the presence of a hepatic leptin-regulated HDL receptor, which regulates HDL-C levels by mediating holoparticle uptake into liver cells[43].

Adjustment of hepatic lipase to HDL in liver cancer

HDL plays a key role in the lipids of binding and delivery, and is a key enzyme in lipoprotein adjustment. Hepatic lipase (HL) hydrolyzes phospholipids and triglycerides in all lipoprotein classes[44,45]. HL is a lipolytic enzyme involved in the metabolism of plasma lipoproteins, especially HDLs[46].

Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels[47]. HL may hydrolyze phospholipids of surface layers from HDL and plasma membrane and thereby enable the flux of cholesteryl esters from the lipoprotein core into the plasma membrane[48,49].

It is important role of hepatic triacylglycerol lipase (H-TGL) in promoting the liver uptake of HDL free and esterified cholesterol[50]. But hepatic lipase can enhance the delivery of high-density lipoprotein cholesterol to cells by a process which does not involve apoprotein catabolism[51]. Hepatic lipase (HL) gene transcription is almost exclusively limited to hepatocytes[52]. Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters[53]. Approximately 28% of the HDL phosphatidylcholine was hydrolyzed by the hepatic lipase. The stimulation of free cholesterol delivery was dose-dependent up to a level of 100 micrograms of HDL free cholesterol/ml of extracellular medium, and was directly related to the extent of phosphatidylcholine hydrolysis. The enhanced cellular accumulation of HDL free cholesterol observed with hepatic lipase appears to be due to the phospholipase activity of this enzyme[54].

Hepatic lipase stimulates the internalization of apoprotein (apo) B-containing lipoproteins by hepatocytes independent from lipolysis. In this study, the role of HL in the hepatic metabolism of apo A-I-containing lipoproteins, i.e. HDL, was investigated. To explore the role of these molecules for the HL effect on selective CE 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%[53].

The inverse correlation between HL activity and HDL-C[55], is due to hepatic lipase stimulation of the uptake of high density lipoprotein cholesterol by hepatoma cells[54]. Hepatoma cells exposed to hepatic lipase-modified HDL, showed an increased uptake of HDL free cholesterol relative to cells exposed to control HDL[30].

Regulation HDL in liver cancer by protein kinase

Protien kinase C is a key molecule in signal transduction pathway, and significant control role in cell growth and deterioration[56]. It plays an important role in many of HDL effects on cells[57]. There is close correlation between carcinogenesis in liver and abnormalities in PKC-α abnormality expression[58,59]. HDL receptor-mediated translocation and efflux of intracellular cholesterol occurs through activation of protein kinase C[60]. Activation of protein kinase C enhances and inhibition of PKC suppresses apolipoprotein-mediated cholesterol efflux[60,61]. High density lipoprotein stimulates multiple signaling pathways. HDL-induced activation of the mitogen-activated protein kinase (MAPK) pathway can be mediated by protein kinase C[62], and high expression in liver tissue[56].

PROSPECT

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[63]. Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful[23]. It may be a good indicator of the hepatic protein synthetic ability during the perioperative period after hepatectomy[64]. Drinking instant coffee powder, in addition to increased uptake HDL-cholesterol, resulted in amelioration of abnormal lipoprotein profiles occurred in hepatoma-bearing rats and has the ability to induce cell cycle arrest and apoptosis in hepatoma cells and to suppress tumor cell invasion. It could also exhibit these effects that lead to the inhibition of tumor growth and metastases[65]. High density lipoprotein as a potential carrier for delivery of a lipophilic antitumoral drug into hepatoma cells[66], to supply a new treatment method in liver cancer.