Hepatitis C Virus Diversity and Hepatic Steatosis

P. Roingeard


J Viral Hepat. 2013;20(2):77-84. 

In This Article

Molecular Mechanisms of HCV-induced Steatosis

The close association of HCV with steatosis should probably be analysed in the light of the evidence from many basic studies demonstrating that the virus hijacks the lipid-producing machinery of the hepatocyte for its own benefit. In cell culture, the HCV core protein associates with lipid droplets (LD),[11] inducing the clustering and accumulation of these lipid storage organelles.[12,13] This LD clustering and accumulation might be the consequence of a decrease in LD turnover induced by the interaction of the HCV core protein with a host cell enzyme that synthesizes triglycerides in the ER, the diacylglycerol acyltransferase 1 (DGAT1).[14,15] HCV virions are then formed at endoplasmic reticulum (ER) membranes directly apposed to these clustered LD,[16,17] suggesting that virus-induced steatosis may be a consequence of viral lifecycle strategy.[18] HCV particles are then secreted and circulate as very low-density lipoprotein (VLDL)–virus complexes rich in triglycerides.[19] These particles, which are known as lipoviro particles (LVPs), contain viral RNA, viral structural proteins (core and envelope E1 and E2 proteins) and the host-derived apolipoproteins B and E (apoB and apoE).[19]

Specific mechanisms have been proposed to account for virally induced steatosis. These mechanisms involve decreases in the levels of microsomal triglyceride transfer protein (MTP), and peroxisome proliferator-activating receptors (PPARs), increases in sterol regulatory element–binding protein (SREBP) levels, oxidative stress due to the production of reactive oxygen species (ROS) and phosphatase and tensin homologue (PTEN) downregulation (Fig. 2).

Figure 2.

Schematic diagram of the principal mechanisms put forward to account for lipid accumulation in HCV-infected hepatocytes. HCV interferes with the production and/or activity of microsomal triglyceride transfer protein (MTP), a luminal ER protein involved in very low-density lipoprotein (VLDL) assembly and export. HCV inhibits transcription of the gene encoding peroxisome proliferator-activating receptor α (PPARα), a nuclear factor downregulating the synthesis of enzymes involved in fatty acid β-oxidation, such as carnitine palmitoyltransferase I. HCV activates sterol regulatory element-binding protein 1c (SREBP-1c), a nuclear transcription factor controlling the expression of genes encoding enzymes involved in fatty acid synthesis. HCV leads to the production of reactive oxygen species (ROS), which induce the peroxidation of membrane lipids and proteins involved in trafficking and secretion, inhibiting VLDL secretion. Mechanisms associated with the inhibition of MTP and PPARα and the activation of SREBP-1c have been shown to be more pronounced in cases of infection with genotype 3 viruses (red lines) than in cases of infection with other genotypes (white lines). HCV genotype 3 has a specific effect not observed with other genotypes, involving inhibition of the transcription of the phosphatase and tensin homologue (PTEN) gene. Arrows indicate increases or activation, whereas blunt ends indicate inhibition.


Microsomal triglyceride transfer protein (MTP), which is present in the ER lumen, stabilizes apoB by lipidation. Lipidated apoB binds triglycerides, forming VLDL for export from hepatocytes. HCV core[20] and nonstructural proteins[21] have been shown to decrease the activity of MTP, resulting in the accumulation of intracellular lipids due to a decrease in VLDL export. Several studies have reported low serum triglyceride concentrations in patients chronically infected with HCV.[22] In human liver biopsy specimens, MTP mRNA levels are inversely correlated with the degree of hepatic steatosis, regardless of HCV genotype.[23] However, patients infected with genotype 3 viruses have significantly lower levels of MTP activity than patients infected with other genotypes,[23] suggesting that genotype 3 viral proteins may also directly inhibit MTP activity.


The PPAR nuclear receptors belong to the steroid superfamily. PPARα is strongly expressed in hepatocytes, in which it regulates lipid metabolism through fatty acid import into mitochondria and the activation of oxidative enzymes. Decreases in PPARα activity probably cause fatty acid uptake and a decrease in mitochondrial oxidation, resulting in hepatic steatosis. Liver biopsy specimens from patients with chronic HCV infection have been shown to contain lower levels of PPARα and its target gene transcripts than specimens from controls.[24] More detailed analyses have shown that PPARα mRNA levels are even lower in patients infected with genotype 3 viruses than in those infected with genotype 1 viruses,[25] suggesting that this inhibition may also involve genotype-dependent mechanisms.


Sterol regulatory element–binding proteins (SREBPs) constitute a family of ER membrane-associated transcription factors that regulate the production of enzymes involved in lipogenesis. The SREBP-1c isoform is produced predominantly in the liver. In its inactivated form, it binds the SREBP cleavage-activating protein (SCAP). Low intracellular sterol concentrations lead to cleavage from SCAP, the resulting SREBP being translocated to the nucleus (nuclear SREBP; nSREBP), where it binds to the SREBP response element (SRE), upregulating the transcription of genes involved in lipogenesis. Various methods accounting for the increase in lipogenesis due to SRBP activation by HCV have been described in cellular models in vitro. SREBP mRNA levels increase in cells producing the HCV core protein, resulting in an increase in fatty acid synthesis within hepatocytes.[26] It was shown in an in vitro study that fatty acid synthetase (FAS) was more strongly induced, in an SRBP1c-dependent manner, by genotype 3 core proteins than by genotype 1 core proteins.[27] However, these results were called into question by a study reporting a lack of specific increase in the expression of genes involved in lipogenesis following SREBP activation in the livers of patients infected with genotype 3 viruses.[28] HCV-induced oxidative stress and the subsequent activation of the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway and PTEN inactivation have also been shown to mediate the transactivation of SREBPs.[29] Again, this phenomenon was found to be more marked with genotype 3 core protein than with genotype 1 core protein. Finally, the nonstructural NS2 protein has also been shown to activate SREBPs in human hepatic cell lines.[30]

Oxidative Stress

Hepatitis C virus core protein directly increases the level of ROS products by inhibiting electron transport and modifying mitochondrial permeability.[31,32] This ROS production leads to the peroxidation of membrane lipids and proteins involved in trafficking and secretion, inhibiting VLDL secretion. In addition to the direct effects of HCV proteins on the mitochondria, HCV-induced immune activation may also cause oxidative stress through cytokine release and macrophage activation. Moreover, the release of proinflammatory cytokines, such as tumour necrosis factor α (TNFα), further promotes insulin resistance, which may in turn favour the development of hepatic steatosis.


A new mechanism specifically attributable to the HCV core protein of genotype 3 isolates has recently been proposed.[33] PTEN, the intrahepatic downregulation of which has been shown to contribute to the development of steatosis in NAFLD, has been shown to be downregulated by a genotype 3 core protein in cellular models in vitro, via a mechanism involving a microRNA-dependent blockade of PTEN mRNA translation. By contrast, no such effect is observed with genotype 1 core protein.