Hepatitis C virus HCV is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, hepatitis c and cholesterol, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia.
Furthermore, virus production is dependent on hepatic very-low-density lipoprotein VLDL assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles.
Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune hepatitis c and cholesterol, and hijacking host factors for HCV maturation and secretion.
Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride hepatitis c and cholesterol, and the molecular mechanisms underlying these effects. This presents a major health problem, hepatitis c and cholesterol, as HCV infection is a leading cause of chronic hepatitis, hepatitis c and cholesterol cirrhosis, and liver cancer worldwide.
Chronic HCV infection is typified by slow progression to cirrhosis and advanced liver disease. Many individuals, who acquired the infection as young adults in the s, are now presenting with serious liver disease, resulting in an increasing prevalence of hepatocellular carcinoma and cirrhosis over the past decade [ 2 ]. The recently developed DAAs are becoming a new arm for the standard treatment for HCV and promise to increase therapeutic efficacy significantly [ 1345 ], but these options are still limited by the emergence of resistance mutations.
Treatments to date are specifically aimed at genotype 1 HCV infection, leaving a large swath of patients without effective treatment. Furthermore, those patients who did not respond favorably to the current standard treatment have a decreased response rate to DAAs [ 6hepatitis c and cholesterol, 7 ].
Therefore, while a new era of HCV treatment is on the horizon, the pathogenesis and disease resulting from HCV infection remain critical issues that need to be addressed. Even before the isolation of Hepatitis c and cholesterol as the viral agent causing non-A non-B hepatitis, it was known that this pathologic agent had a unique interaction with lipids and lipoproteins. Most notably, the accumulation of neutral lipids in cytosolic lipid droplets in hepatocytes was defined as a pathologic hallmark of hepatitis C virus infection [ 8 ].
Early biophysical characterizations of virus particles in patient serum also revealed the virus to be highly heterogenous in buoyant density due to association with host lipoproteins [ 910 ]. The lipoprotein association of the virus particle was examined further both from human serum and from particles developed from hepatoma cells in cell culture HCVcc. These characterizations have revealed virus particles that have both aspects of typical virions and aspects more similar to host-lipoproteins.
These infectious hybrid particle complexes have been termed lipoviral particles LVP to highlight their complex nature Figure 1. Since the HCV virion utilizes lipoproteins in such a unique way, lipoprotein metabolism research has illuminated understanding of the virus-host interactions of HCV. We outline here some of the most intriguing results of the role of cholesterol and other lipids in HCV pathogenesis, and describe their role in the steps of the HCV life cycle including entry, replication, and assembly.
The functions of these proteins are analogous: C Hepatitis C virus HCV particles in patient sera circulate in complexes with host lipoproteins as lipoviral particles, which are enriched in triglyceride, cholesterol, and several apolipoproteins [ 2223 ], hepatitis c and cholesterol. Clinical evidence indicates that HCV infection is not only intimately linked to the metabolism of lipids within the hepatocytes that HCV infects, but dysregulates circulating lipoprotein metabolism as well.
The liver hepatitis c and cholesterol the central organ of lipid homeostasis for the entire body, through production and uptake of lipoproteins. Triglycerides TG are packaged in lipoproteins surrounded by a phospholipid, cholesterol, and amphipathic protein monolayer to deliver lipids produced or absorbed from the liver and intestine respectively to other organs Figure 1.
While HCV hijacks elements of the very-low density lipoprotein VLDL secretion pathway for the production of infectious particles, the LVP that circulate in an infected individual indicate that HCV virions are not only associated with hepatically derived triglyceride-rich lipoproteins TRL containing apoB, but are also associated with intestinally derived lipoproteins containing apoB [ 1112 ], an isoform of apoB exclusively generated from the small intestine.
The presence of this subpopulation of LVP indicates an active exchange of virions between lipoproteins [ 12 ].
Aside from infectious LVP, HCV envelope proteins have been detected on the surface of lipoproteins devoid of infectious nucleocapsids, in so called empty LVP eLVPpossibly contributing to the physiopathology of the disease [ 13 ].
The functional advantage of the association of virions with host lipoproteins has not been completely hepatitis c and cholesterol, though evidence suggests utilization of lipoprotein components may both mediate attachment to lipoprotein receptors, and obscure circulating viral particles from immunoglobulin recognition, thereby allowing the virus to escape immune surveillance [ 1415 ].
It must be determined whether these mechanisms are clear priorities, given the implications in vaccine design and the possibility that abrogating these mechanisms may have important clinical significance in preventing infection post-liver transplantation [ 1617 ]. Aside from the physical association of HCV components with lipoproteins, intracellular lipids play key roles throughout the HCV life cycle.
Chronic HCV infection is associated with deregulated lipid homeostasis favoring triglyceride accumulation in the liver [ 2425 ]. HCV infection may contribute to this accumulation through transcriptional activation of lipogenic genes favoring lipid synthesis in patients [ 2627 ].
HCV infected chimpanzees likewise revealed transcriptional induction of these genes via activation of sterol response element binding proteins SREBPsimportant transcription factors involved in cholesterol and fatty acid regulation [ 28 ]. However, clinical studies have indicated that HCV induced overexpression of lipogenic genes may exert a strong influence on inflammation and fibrosis progression of the infected liver, rather than causing the lipid accumulation observed in hepatic steatosis [ 34 ].
Sophisticated stable-label studies indicate that patients with HCV infection have increased fatty acid synthesis and diminished cholesterol synthesis compared to uninfected individuals [ 35 ]. While the studies are limited by patient numbers, stable-label studies may further illuminate HCV-associated metabolic disturbances in future studies, hepatitis c and cholesterol. This correlation is particularly strong in genotype 3 infection relative to other genotypes, suggesting genetic variation of HCV contributes to lipid accumulation.
Further evidence of a direct effect of the virus is the fact that the steatotic grade correlates with the HCV RNA quantity present both in the liver [ 24 ], and in the serum of hepatitis c and cholesterol patients [ 3839 ]. Those patients with HCV infection who manifest steatosis, hepatitis c and cholesterol, are also more likely to present hypobetalipoproteinemia diminished serum levels of apoB bearing lipoproteins and diminished serum cholesterol levels [ 253640hepatitis c and cholesterol, 41 ].
These observations indicate that HCV associated steatosis may be a sequela of diminished triglyceride export by modulated apolipoprotein B bearing lipoprotein production [ 25 ]. There is a correlation of HCV genotype 3 infection with both steatosis and hypocholesterolemia [ 25 ]. Recent metabolomic analysis also indicates that genotype 3 HCV infection inhibits cholesterol synthesis as there is a lack of late step intermediate metabolites in patients infected with genotype 3, but not genotype 2 HCV [ 42 ].
Indeed, the rate-limiting enzyme of VLDL production, microsomal triglyceride transfer protein MTPis transcriptionally repressed by HCV gene expression both in vitro [ 43 ], and in vivo [ 44 ], and associates with steatosis [ 44 ].
Recent studies suggest that the virus-induced dysregulation of apoB secretion is mediated by increased ferritin heavy chain levels [ 45 ]. Indeed, an inverse correlation between ferritin and secreted apoB concentrations is found both in JFH-1 HCVcc and HCV-infected patients, indicating a possible explanation for the onset of virus-induced liver steatosis [ 45 ]. Steatosis is not only caused by HCV, but is also linked to pathogenesis and enhanced disease progression.
Chronic HCV infection is also strongly hepatitis c and cholesterol with insulin resistance, which might be a consequence of impaired insulin signaling and activation of inflammatory markers such as TNF-alpha and the suppressor of cytokine signaling SOCS family proteins. This in turn deregulates fatty acid synthesis and leads to hepatic steatosis. In parallel, the HCV core protein increases the activity of peroxisome proliferator-activating receptor PPAR —alpha and gamma in hepatocytes contributing to deregulation of fatty acid beta-oxydation and insulin sensitivity for a review see [ 46 ].
Finally, Fujino et al. The viral effect on patient serum lipid profile has recently been confirmed in a large scale study in China including 11, patients that reported HCV viremia statistically associating with lower serum cholesterol and TG levels [ 47 ]. This pathology can also be observed in transgenic mice expressing the HCV polyprotein [ 30 ]. Diminished triglyceride levels may also play an important role in the severity of the infection, since an Egyptian study highlighted that high circulating TG levels during acute infection associates with spontaneous clearance of HCV [ 41 ].
Biochemical analysis of HCVcc using a purification scheme involving an epitope tagged envelope protein displayed apoE on the virion surface [ 49 ].
Three isoforms of apoE are present in the human population, determined by cysteine residue substitutions at positions andhepatitis c and cholesterol E2, E3 and E4. Given the primary role of apoE in the HCV life cycle, several studies investigated the possibility of a correlation between apoE isoform and hepatitis C infection.
Using the HCVcc system, it remains controversial, but apoE genotype seems to have little effect in altering infectivity [ 5152hepatitis c and cholesterol, 5354 ].
Comparison of genotype and allele distribution with those hepatitis c and cholesterol healthy controls yielded evidence of diminished progression of liver disease and viral clearance associated with the E2 allele, which may protect against establishment of chronicity via defective binding of LVP to the cellular receptors involved in HCV entry [ 55 ].
Studies have suggested important roles in HCV infection played by single nucleotide polymorphisms of host genes involved in lipid metabolism, such as LDLr [ 58 ] and apoB, however these studies were limited by population size and conclusive results await the confirmation of larger-scale studies. As previously mentioned, HCV directly affects the composition of host circulating lipoproteins of HCV positive patient sera, for example through the generation of eLVP.
These altered lipoproteins then in turn induce changes in the lipid metabolism of monocyte-derived macrophages [ 59 ]. This may represent a depletion of large HDL particles, providing clinical evidence that HCV and host lipoproteins are reciprocally influenced [ 60 ].
Similarly, Kim et al. Several studies have indicated a link between the successful outcome of antiviral treatment and observed lipid metabolism parameters of the patient. Moreover, hypobetalipoproteinemia and diminished serum cholesterol levels are reversed after effective response to antiviral therapies, indicating the direct role of the virus on cholesterol and LDL levels [ 256667hepatitis c and cholesterol, 68 ].
However, hepatitis c and cholesterol, the decreased cholesterol and LDL levels associated with HCV does not appear to translate into a cardioprotective role, as carotid atherosclerosis is increased in HCV patients, perhaps due to increased insulin resistance and metabolic syndrome [ 69 ]. The association of lipids with peg-interferon treatment response suggests that lipid modulation may be an effective strategy to modify interferon sensitivity [ 7173 ].
The close relationship hepatitis c and cholesterol host lipids and the HCV life cycle generates opportunities of new therapeutic options that target lipid regulation.
Indeed, host factor targeting overcomes viral resistance due to emerging escape variants and genotype variability. Several lipid modulating agents, which were initially tested for their cardioprotective roles, may increase the efficacy of antiviral therapies, such as insulin sensitizing drugs and statins.
Since insulin resistance hepatitis c and cholesterol steatosis can modify antiviral treatment outcome, and since IR and steatosis enhance progression of the disease, it has been proposed to combine standard of care treatment and administration of insulin sensitizer such as metformin [ 74 ] or thiazolidinedione to manage insulin resistance and in turn induce a SVR [ 7576 ]. Statins are inhibitors of 3-hydroxymethylglutaryl coenzyme A reductase HMGCRa limiting step of cholesterol synthesis, and are widely used to modulate cholesterol levels in patients at risk of heart disease, or with familial hypercholesterolemia.
The combination of statins with standard of care treatment can decrease hepatic steatosis and improve standard of care treatment efficacy [ 77hepatitis c and cholesterol, 7879 ]. Despite promising effects observed in in vitro studies [ 80 ], the administration of statins alone lead to contradictory effects on HCV viral load [ 81hepatitis c and cholesterol, 828384 ].
Other strategies are under investigation in clinical trials, such as combination with PPAR agonists, antagonists, or nicotinic acid. Promising lipid modulating results in humanized mice and chimp models have indicated utility for apoB antisense miRNA mipomersen [ 88 ] or micro-RNA miR antagonists [ 89 ] for their clinical utility as antivirals [ 90 ].
However, proof-of-concept studies for HCV therapy remains to be determined. Moreover, natural compounds that affect lipid metabolism such as the grapefruit flavonoid naringenin [ 9192 ] as well as Epigallocatechingallate EGCGan anti-oxidant molecule isolated from the green tea show an antiviral effect. EGCG inhibits HCV entry at the viral attachment step [ 9394 ], and EGCG and derivatives also inhibits viral replication via cyclooxygenase 2 and can decrease viral induced inflammation [ 95 ].
Green tea compounds as well as naringenin may act as interesting natural complement diet to lower the progression of HCV induced liver disease, however in vivo clinical trial data are yet not available.
Viral particles purified from patient sera were observed for the first time by electromicroscopy in [ 96 hepatitis c and cholesterol. The particles observed were spherical and heterogeneous in size and density, corroborating previous findings [ 979899 ], and confirmed later by several other groups [ 2223], hepatitis c and cholesterol. Hepatitis c and cholesterol analysis using sucrose gradients of infected patients sera further showed that HCV RNA is distributed over a wide range of densities from 1.
The fractions containing the highest amount of RNA are between 1. Density heterogeneity is in part explained by association of the virus both with immunoglobulins [ 22] and different lipoprotein classes [ 910222397, ].
Associations with lipoproteins were hepatitis c and cholesterol confirmed by immunoprecipitation of the HCV RNA containing fractions with anti-apolipoprotein antibodies against apoB [ 923 ] or apoE [ 2223 ]. A major advance in Muscle loss and weight research occurred in with the discovery that the highly replicative HCV JFH1 strain, was capable of producing infectious virions from select hepatoma cell lines in culture [, ].
Analysis of HCVcc largely confirmed previous observations obtained with human sera regarding density and size heterogeneity as well as the LVP nature of the HCVcc [ ]. This can be explained at least in part by the differences in the neutral lipid content of the LVP produced in cell culture vs. Density may also vary based on the cell type producing the virus [, ].
Hepatitis c and cholesterol, LVP produced in human liver engrafted mice [ ], as well as in primary human hepatocytes [ ], more closely resemble particles purified from patients infected with HCV. HCVcc passaged through different animal models or cell types revealed a higher specific infectivity of the lowest-density populations [,].
However, engineering of cells to produce a majority of VLDL does not radically change the virus distribution to low-density, indicating a possible genetic contribution for LVP formation [ ]. Analysis hepatitis c and cholesterol the lipid composition of the HCVcc particles revealed similar composition to LDL and VLDL, in cholesterol, cholesteryl esters, phospholipids, and sphingolipids [ 49, ].
The presence of apolipoproteins such as apoE, apoB, apoCI, apoA1 have also been reported to be HCVcc components through immunoprecipitation studies [ 1122hepatitis c and cholesterol, ].
It is noteworthy that apolipoproteins play an important role in HCV entry, assembly, and export steps [ 4960,]. Apolipoprotein content analysis of purified HCVcc showed that each particle bears approximately molecules of apoE at its surface [ 49 ], a remarkable enrichment since hepatitis c and cholesterol estimates of apoE molecules per VLDL are 5—7 [ ]. Furthermore, recent evidence suggests that basic residues of HCV E2 protein may be important for the infectivity of low-density particles [ ].