Portal de Periódicos da CAPES

HCV Infection and Metabolic Syndrome: Which Is the Chicken and Which Is the Egg?

2012; Elsevier BV; Volume: 142; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2011.12.063

1528-0012

Francesco Negro,

Diabetes, Cardiovascular Risks, and Lipoproteins

Hepatitis C virus (HCV) causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma.1European Association for the Study of the LiverEASL Clinical Practice Guidelines: management of hepatitis C virus infection.J Hepatol. 2011; 55: 245-264Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar The World Health Organization estimates that approximately 2.35% of the world population (∼160 million individuals) is infected with HCV.2Lavanchy D. Evolving epidemiology of hepatitis C virus.Clin Microbiol Infect. 2011; 17: 107-115Abstract Full Text Full Text PDF PubMed Scopus (1047) Google Scholar Another widespread disorder, metabolic syndrome, comprises a group of correlated clinical features that have insulin resistance as a common pathogenic determinant; it can lead to type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular disorders, and many types of cancer, including hepatocellular carcinoma.3Alberti K.G. Eckel R.H. Grundy S.M. et al.Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (11009) Google Scholar, 4Larsson S.C. Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.Br J Cancer. 2007; 97: 1005-1008PubMed Google Scholar Metabolic syndrome is pandemic; its estimated prevalence in the United States is ∼25%.5McCullough A.J. Epidemiology of the metabolic syndrome in the USA.J Dig Dis. 2011; 12: 333-340Crossref PubMed Scopus (113) Google Scholar It is important to determine the relationship between HCV infection and metabolic syndrome. There is no evidence for an association between HCV infection and metabolic syndrome (that the 2 conditions occur together at a higher rate than would occur by chance) or other features of metabolic syndrome, such as arterial hypertension or visceral obesity,6Shaheen M. Echeverry D. Oblad M.G. et al.Hepatitis C, metabolic syndrome, and inflammatory markers: results from the Third National Health and Nutrition Examination Survey [NHANES III].Diabetes Res Clin Pract. 2007; 75: 320-326Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar although HCV infection has been associated with type 2 diabetes mellitus.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar The serum lipid profile of patients with HCV infection is characterized by decreased levels of cholesterol and sometimes triglycerides,8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar in contrast to that of metabolic syndrome. HCV infection appears to interact with some aspects of lipid and glucose metabolism, but it is not clear which event occurs first (as in the chicken or egg story). This is an important issue to resolve, because there is evidence that HCV infection not only causes steatosis,8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar but also accelerates the development of type 2 diabetes mellitus in predisposed individuals.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar Furthermore, some data indicate that patients with HCV infection benefit from the metabolic, cytokine, and adipokine profile of metabolic syndrome. Therefore, if HCV and metabolic syndrome are not associated, they certainly interact. HCV infection might cause fatty liver. The incidence of steatosis is about 2-fold greater among individuals with chronic HCV than those with chronic hepatitis B virus infection8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar; before the availability of serologic tests for hepatitis C, the presence of steatosis was a diagnostic criterion of non-A, non-B hepatitis. Fatty liver is more frequent and severe in patients infected with HCV genotype 3, and the degree of steatosis correlates with viral load; the virus disappears (or fails to do so) in patients who respond to antiviral therapy (or do not respond).8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar Several mechanisms have been proposed to account for the accumulation of lipids in hepatocytes (Figure 1). HCV seems to interfere with the assembly of very-low-density lipoproteins (VLDL) by reducing the activity and/or the expression of the microsomal triglyceride transfer protein (MTTP).8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 9Mirandola S. Realdon S. Iqbal J. et al.Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis.Gastroenterology. 2006; 130: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar Furthermore, HCV might stimulate the synthesis of cholesterol and fatty acids via activation of the steroid responsive element binding proteins 1c and 2, important regulators of lipidogenesis.10Waris G. Felmlee D.J. Negro F. et al.Hepatitis C virus induces the proteolytic cleavage of sterol regulatory element binding proteins (SREBPs) and stimulates the phosphorylation of SREBPs via oxidative stress.J Virol. 2007; 81: 8122-8130Crossref PubMed Scopus (225) Google Scholar Intermediates of cholesterol biosynthesis, such as geranylgeranyl pyrophosphate, are required for HCV replication, as are lipid rafts, which are rich in cholesterol; inhibition of cholesterol synthesis by statins suppresses HCV replication.11Kapadia S.B. Chisari F.V. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids.Proc Natl Acad Sci U S A. 2005; 102: 2561-2566Crossref PubMed Scopus (462) Google Scholar HCV assembly starts at the surface of lipid droplets (LDs), small lipid-storing organelles found in the cytoplasm of healthy hepatocytes. HCV hijacks the host lipoprotein assembly and secretion pathways for virion export.12Syed G.H. Amako Y. Siddiqui A. Hepatitis C virus hijacks host lipid metabolism.Trends Endocrinol Metab. 2010; 21: 33-40Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar As a result, circulating virions are complexed with lipoproteins in low-density lipoviroparticles, which facilitates reuptake by hepatocytes by docking to the low-density lipoprotein receptor.8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar Lipids therefore have several important roles in HCV replication and virion assembly, and any pathophysiological event that affects lipid metabolism could affect the HCV life cycle. What is the effect of steatosis on HCV infection, if any? HCV has been reported to induce steatosis by impairing the function of MTTP, an enzyme implicated in VLDL assembly. Blocking the VLDL secretion pathway by inhibiting MTTP with naringenin reduces export of HCV.13Nahmias Y. Goldwasser J. Casali M. et al.Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin.Hepatology. 2008; 47: 1437-1445Crossref PubMed Scopus (231) Google Scholar It is puzzling that HCV induces steatosis by interfering with cell pathways so important to its life cycle. Studies that tested the in vitro effects of HCV on the expression of proteins associated with LD physiology showed that HCV increases the expression of seipin, a protein implicated in maturation and fusion of LDs.14Clément S. Fauvelle C. Pascarella S. et al.Hepatitis C virus and lipid droplets: role of seipin in lipid droplet maturation and viral life cycle.J Hepatol. 2011; 54: S311Abstract Full Text PDF PubMed Google Scholar Overexpression of seipin in hepatoma cells subsequently infected with HCV caused a significant decrease in virion export, accompanied by the appearance of large LDs (and in the absence of increased triglyceride levels). Careful morphologic characterization of this experimental steatosis showed that the decrease in virion export correlated with the decrease in LD surface area, a phenomenon one would expect when numerous small LDs are fused into bigger ones.14Clément S. Fauvelle C. Pascarella S. et al.Hepatitis C virus and lipid droplets: role of seipin in lipid droplet maturation and viral life cycle.J Hepatol. 2011; 54: S311Abstract Full Text PDF PubMed Google Scholar If confirmed, these observations indicate that steatosis, rather than factors that regulate the spread of HCV, may be a mechanism of viral restriction, reducing the surface area of organelles where virion assembly begins. Although patients with HCV genotype 3 and steatosis have higher viral loads, the increase in viral load precedes fat accumulation (rather than the other way around), as shown by clinical trials of antiviral therapies.15Poynard T. Ratziu V. McHutchison J. et al.Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C.Hepatology. 2003; 38: 75-85Crossref PubMed Scopus (550) Google Scholar Furthermore, the same studies have shown that the viral steatosis associated with HCV genotype 3 does not reduce the response to antiviral therapy.15Poynard T. Ratziu V. McHutchison J. et al.Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C.Hepatology. 2003; 38: 75-85Crossref PubMed Scopus (550) Google Scholar Therefore, there does not appear to be evidence that steatosis per se promotes HCV infection. In addition, there is no conclusive evidence that HCV-induced steatosis affects the outcomes of metabolic syndrome, such as by increasing the incidence of cardiovascular events.8Bugianesi E. Salamone F. Negro F. The interaction of metabolic factors with HCV infection: does it matter?.J Hepatol. 2012; 56: S56-S65Abstract Full Text PDF PubMed Scopus (158) Google Scholar Like metabolic syndrome, HCV is associated with insulin resistance.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar Glucose metabolism is altered during early stages of chronic hepatitis C to a significantly greater extent than in patients with chronic hepatitis B.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar Patients with chronic hepatitis C are insulin resistant before they develop advanced fibrosis, and individuals with HCV infection who are predisposed to develop type 2 diabetes mellitus do so at least one decade earlier those without HCV infection.16Mehta S.H. Brancati F.L. Sulkowski M.S. et al.Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States.Ann Intern Med. 2000; 133: 592-599Crossref PubMed Scopus (618) Google Scholar The reduction of viral load that follows treatment with danoprevir, an HCV serine protease inhibitor, is paralleled by a reduction in insulin resistance.17Moucari R. Forestier N. Larrey D. et al.Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in genotype 1 chronic hepatitis C patients.Gut. 2010; 59: 1694-1698Crossref PubMed Scopus (56) Google Scholar Furthermore, eradication of HCV infection is associated with reduced incidence of glucose metabolism disturbances after treatment, independently of other predisposing factors.18Arase Y. Suzuki F. Suzuki Y. et al.Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C.Hepatology. 2009; 49: 739-744Crossref PubMed Scopus (239) Google Scholar HCV infection therefore causes insulin resistance, which can progress to type 2 diabetes mellitus in susceptible persons. Many different mechanisms contribute to HCV-induced insulin resistance (Figure 2). HCV infects the liver, so it seems obvious to investigate whether HCV directly interferes with insulin signal transduction pathways in hepatocytes.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar However, insulin resistance has also been shown to originate in organs outside the liver, essentially in striated muscle.19Vanni E. Abate M.L. Gentilcore E. et al.Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C.Hepatology. 2009; 50: 697-706Crossref PubMed Scopus (143) Google Scholar It is not clear how HCV affects the insulin responsiveness of tissues that it does not infect. Interestingly, the adipose tissue does not appear to be involved in the pathogenesis of viral insulin resistance; free fatty acid efflux from adipose tissue responds to insulin in normal persons and in patients with chronic hepatitis C, as shown by euglycemic hyperinsulinemic clamp analyses.19Vanni E. Abate M.L. Gentilcore E. et al.Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C.Hepatology. 2009; 50: 697-706Crossref PubMed Scopus (143) Google Scholar Regardless of the mechanism (viral or linked to metabolic syndrome), does insulin resistance promote HCV infection? There is only a small amount of evidence for a correlation between insulin resistance and viral load. Reducing insulin resistance with pioglitazone in patients with chronic hepatitis C does not produce significant changes in viral load.20Harrison S.F. Hamzeh M. Lentz E. et al.Virologic and metabolic responses in chronic hepatitis C (CHC) patients with insulin resistance (IR) treated with pioglitazone and peginterferon alpha-2a plus ribavirin.J Hepatol. 2010; 52: S129Abstract Full Text PDF Google Scholar On the other hand, insulin resistance reduces patients' response to interferon (IFN)-α–based regimens; patients with higher levels of insulin resistance, measured by a homeostasis assessment of insulin resistance, have lower rates of response.21Deltenre P. Louvet A. Lemoine M. et al.Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis.J Hepatol. 2011; 55: 1187-1194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar However, insulin resistance has not been proven to directly cause the lack of response to IFN-α therapy. Correction of insulin resistance with pioglitazone does not improve patients' response to combination therapy with pegylated IFN-α and ribavirin.20Harrison S.F. Hamzeh M. Lentz E. et al.Virologic and metabolic responses in chronic hepatitis C (CHC) patients with insulin resistance (IR) treated with pioglitazone and peginterferon alpha-2a plus ribavirin.J Hepatol. 2010; 52: S129Abstract Full Text PDF Google Scholar One study showed that metformin nonsignificantly increased the rate of sustained virologic response in patients with HCV infection,22Romero-Gómez M. Diago M. Andrade R.J. et al.Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin.Hepatology. 2009; 50: 1702-1708Crossref PubMed Scopus (137) Google Scholar but these findings have not yet been confirmed. It was proposed that the insulin resistance that accompanies metabolic syndrome, rather than the HCV-induced insulin resistance, reduces patients' response to IFN-α.21Deltenre P. Louvet A. Lemoine M. et al.Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis.J Hepatol. 2011; 55: 1187-1194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar HCV-associated insulin resistance might just be a marker of an unknown molecular event that is induced by HCV that reduces a patient's response to IFN-α. The rationale of reducing insulin resistance just to increase the response to treatment seems unfounded. All in all, there is little evidence that insulin resistance per se promotes HCV infection. Little is known about how metabolic syndrome affects HCV infection. The formation of large LDs, as observed in fatty liver, does not appear to promote the HCV life cycle. On the other hand, the insulin resistance that develops in patients with metabolic syndrome (but not HCV-induced insulin resistance) is associated with increased release of free fatty acids from adipose tissue; in vitro studies showed that incubation of hepatoma cells with free fatty acids stimulated HCV replication.11Kapadia S.B. Chisari F.V. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids.Proc Natl Acad Sci U S A. 2005; 102: 2561-2566Crossref PubMed Scopus (462) Google Scholar Moreover, metabolic syndrome is associated with the activation of transcription factors in hepatocytes that increase lipogenesis, which would provide HCV with important metabolites necessary for replication.23Caballero F. Fernández A. De Lacy A.M. et al.Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.J Hepatol. 2009; 50: 789-796Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar Some pathophysiological changes associated with metabolic syndrome are therefore likely to promote the HCV life cycle. Metabolic syndrome is characterized by production of cytokines that can affect the relationship between HCV and its host. The adipose tissue has important endocrine functions; it secretes humoral factors that control metabolism, energy homeostasis, and the immune response. Some of these factors have anti-inflammatory and antiadipogenic activity, whereas others have opposing, proinflammatory, and proadipogenic effects. Although some factors are cytokines that are mostly produced by inflammatory cells, such as tumor necrosis factor α and interleukin-6, others are typically secreted by adipocytes and collectively referred to as adipokines (such as leptin and adiponectin). Leptin is an important hormone that regulates innate and adaptive immune responses under normal and pathologic conditions. Reduced production of leptin and increased resistance to leptin have been associated with altered immune responses and increased susceptibility to infection. Reduced serum concentrations of leptin can lead to immune suppression,24Lord G.M. Matarese G. Howard J.K. et al.Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.Nature. 1998; 394: 897-901Crossref PubMed Scopus (1886) Google Scholar as can leptin resistance; ob/ob mice (do not produce leptin) and db/db mice (do not produce leptin receptor) have immune deficiencies observed during starvation.25Howard J.K. Lord G.M. Matarese G. et al.Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.J Clin Invest. 1999; 104: 1051-1059Crossref PubMed Scopus (474) Google Scholar Circulating levels of leptin have been variably associated with some features of chronic hepatitis C, such as steatosis, advanced fibrosis, and poor response to therapy, although these findings are inconclusive. Patients with metabolic syndrome have normal or higher circulating levels of leptin despite increased food intake, indicating that they are leptin resistant. Leptin resistance is one of several processes that results from activation of SOCS-3, which has been proposed as a marker of poor response to therapy for chronic hepatitis C.7Kaddai V. Negro F. Current understanding of insulin resistance in hepatitis C.Expert Rev Gastroenterol Hepatol. 2011; 5: 503-516Crossref Scopus (47) Google Scholar, 19Vanni E. Abate M.L. Gentilcore E. et al.Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C.Hepatology. 2009; 50: 697-706Crossref PubMed Scopus (143) Google Scholar Although the effects of leptin and other adipokines on the host immune responses against HCV have not been studied, it would be interesting to determine whether one or more adipokines secreted in patients with metabolic syndrome affects their response to therapy. Adipokines might promote the initial infection with HCV, the persistence of infection, or the inability to eradicate the infection once it has become chronic, such as during therapy with IFN-α. There is no evidence for an association between HCV and metabolic syndrome, although features of each disorder appear to synergize to affect patient outcomes. If HCV induces fatty liver and insulin resistance, which speeds the development of type 2 diabetes mellitus in susceptible individuals, the addition of metabolic syndrome might promote HCV replication and blunt HCV-specific immune responses. The public health burden of each epidemic, advanced liver disease from chronic HCV infection and metabolic syndrome, is likely to increase in the next decade. Better mechanistic insights into the molecular interactions between these 2 conditions are needed.