**1. Introduction**

700 Lipoproteins – Role in Health and Diseases

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> Hepatitis C virus (HCV) is a unique virus whose life cycle is closely associated with lipoprotein metabolism [1, 2, 3]. Assembly of HCV particles, formation of HCV-virions, is closely connected to the formation of lipid droplets in hepatic cells that may serve as an assembly platform [1, 4]. In addition, the production of HCV particles is tightly linked to the very low-density lipoprotein (VLDL) production pathway [5, 6]. HCV particles circulating in the blood during chronic HCV infection form lipo-viral particles (LVP) that are rich in triglycerides (TG), apoB-100 and apoE, with physiochemical similarity to VLDL particles and are highly infectious [7, 8]. In contrast, denser HCV particles are less infectious. These data strongly suggest that both viral particles and VLDL are integral components of LVPs with high infective capability. Although LVPs are thought to be assembled in liver cells by association with host lipoproteins prior to secretion, association between HCV and VLDL in the circulation after secretion from the liver cannot be ruled out.

> Studies to date have indicated that the process of HCV assembly and secretion largely utilizes the VLDL pathway. Therefore, suppression of apoB-100 or apoE also inhibits secretion of HCV. Inhibition of microsomal triglyceride transfer protein (MTP), a critical protein for the initial step of VLDL assembly by co-translational lipidation of apoB-100 [9, 10], inhibits HCV secretion.

> As HCV depends on VLDL pathways for its assembly and secretion, the lipid-rich environment of the liver cell combined with reduced VLDL secretion may be required for efficient assembly and secretion of HCV virions by ensuring the feasibility of co-assembly with VLDL. Hypobetalipoproteinemia, reduced activity of MTP with negative correlation to hepatic steatosis and viral load, is observed in HCV-G3 chronic infection [11]. Secretion of apoB-100 was reduced by HCV nonstructural proteins using the HCV subgenomic replicon expression system and interaction between the HCV NS5A and apoB-100 was observed [12].

© 2012 Aizawa et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In addition, there has been accumulating evidence that the HCV core protein is induced upon the redistribution of lipid droplets, affecting the assembly of both HCV and VLDL [13, 14]. The function of core protein in lipid metabolism has been widely examined including in models of steatosis involving HCV core protein transgenic mice [15]. Findings include reduction in activity of MTP [9] and Tyr164Phe substitution in relation to marked steatosis in HCV-G3 infection [16]. Although the participation of Arg70Gln/His substitution in steatosis of hepatocytes has been proposed [17], the precise connection between hepatic steatosis and HCV-G1b and/or HCV-G2 infection remains unclear.

As mentioned earlier, HCV particles in peripheral blood may associate not only with VLDL, but also with other lipoproteins, especially LDL, since circulating LVPs span a wide range of buoyant gravity and physicochemical characteristics [8, 18]. The association of lipoproteins with HCV particles may be beneficial for HCV through protection against anti-HCV neutralizing antibodies, as the antigenicity of HCV surface proteins is hidden beneath the associated lipoprotein particle [18]. Lipoprotein particles isolated from sera of HCV patients displayed differentially modulated lipid synthesis in human monocyte-derived macrophages in comparison to lipoproteins obtained from normal subjects, suggesting that HCV infection influences the biochemical composition of lipoproteins, thus revealing an alternative influence on lipid metabolism [19]. HCV entry into liver cells may occur through many receptors, including CD81 (direct binding to HCV E2 protein) and claudin-1, both of which act during the later steps of HCV entry [20]. The predominant role of LDL-receptors or remnant receptors is to catch VLDL-derived lipoprotein particles. Meanwhile, SR-BI (a receptor for HDL and oxidized LDL) directly binds HCV E2 protein [21]. Very recently, Nieman-Pick C1-like 1 cholesterol absorption receptor has been reported as a new factor for HCV entry to hepatic cells [22]. Interestingly, lipoprotein lipase, which hydrolyzes VLDL, is reported to increase the binding of LVP to hepatic cells while simultaneously decreasing infection levels of hepatic cells [23].

These findings suggest that examination of serum lipid profiles in chronic HCV infection may be important for understanding the biological features of HCV infection. Compared to normal subjects, low levels of TC, high-density lipoprotein cholesterol (HDL-C) and LDL-C was reported in chronic HCV-G3a infection [24]. However, lipoprotein profiles in infections of genotypes other than HCV-G3 have not been fully described and the data are somewhat conflicted. Moriya et al. indicated that TC levels and apoB, CII and CIII were reduced in HCV-G1b compared with chronic HCV-G2a or hepatitis B virus (HBV) infection [25], while others have not reported such a distinction. In addition, distortion of serum lipid levels has been widely observed in connection with virological outcome of IFN-based antiviral therapy, especially in HCV-G1 infection. Lower LDL-C, HDL-C, TC and/or TG was reported to be a possible predictor for unfavorable response to IFN-based therapy [24, 26, 27]. However, after the discovery of a genetic polymorphism near the human IL28B gene as the most potent predictor of the outcome of IFN-based therapy, the distortion of serum lipid levels is no longer thought to be an independent factor, but rather a confounding variable for predicting therapeutic efficacy [28].

In this chapter, we described the lipoprotein profiles in chronic HCV-G1b infection (the most common genotype in Japan) compared with that in chronic HCV-G2 infection (the second most common genotype in Japan). In addition, the influence of the genetic polymorphism near the human IL28B gene and aa substitutions in the core and NS5A regions of HCV on lipoprotein profiles in chronic HCV-G1b infection was determined.

To examine the serum lipid profiles of many patients, ultracentrifugation was unsuitable. We instead measured serum lipoprotein using HPLC in addition to a conventional laboratory method involving measurement of apolipoproteins. To examine serum LDL-C levels, the Friedwald equation can be used as an indirect calculation method yielding "total cholesterol minus HDL-C minus 0.2 TG. However, the precision of this equation has not been determined in pathological conditions such as chronic HCV infection.
