In this single centre study, obesity was independently associated with non‐response to antiviral therapy in subjects infected with HCV genotype 1. Virtually all obese subjects (87%) had steatosis, underlining the interrelationship between these variables. However, steatosis was also present in 55% of non‐obese subjects. In these latter patients, the presence or severity of hepatic steatosis did not influence the ability to achieve a response to treatment. In support of these findings, a recent study by Bressler and colleagues also demonstrated that obesity but not hepatic steatosis was an independent negative predictor of response to HCV treatment.9
Many previous studies of both standard and pegylated interferon have identified body weight as a factor impacting on treatment response rates.11,12,13,14,31
It remains unclear whether weight based dosing would improve the response rate or whether obesity is associated with a greater degree of resistance to antiviral therapy.1
In this study, we demonstrated that obese subjects infected with HCV genotype 1 had increased hepatic expression of SOCS‐3, a factor that has been shown to inhibit IFN‐α signalling. This relationship between obesity and increased SOCS‐3 expression remained significant after correction for other factors associated with non‐response to treatment.
Importantly, patients with HCV genotype 1 who were NR had significantly higher levels of SOCS‐3 protein expression compared with RES. Engagement of IFN‐α with its receptor activates receptor associated tyrosine kinases that phosphorylate signal transducer and activator of transcription (STAT) factors 1 and 2.32,33
Phosphorylated STAT proteins migrate to the nucleus and induce transcription of several antiviral target genes. This IFN‐α signalling pathway is downregulated by members of the SOCS family of proteins.18,34
SOCS 1 and 3 have been shown to inhibit the tyrosine phosphorylation and nuclear translocation of STAT 1 in response to IFN‐α stimulation and this inhibition occurs at very low levels of SOCS protein expression.35
Several factors, including the HCV core protein,17
and various cytokines36,37
have been shown to induce hepatic SOCS‐3 expression. In chronic HCV, TNF‐α may have a key role in this inhibitory pathway. TNF‐α levels are increased in the serum,38
liver, and peripheral blood mononuclear cells20
of subjects with chronic HCV compared with control subjects. Higher pretreatment intrahepatic19
and peripheral blood mononuclear cell20
TNF‐α mRNA levels were observed in patients who subsequently failed to respond to IFN‐α therapy compared with those subjects who had an SVR. More recently, Hong et al
have shown in a mouse model that injection of TNF‐α markedly induced expression of SOCS‐3, resulting in inhibition of IFN‐α signalling in hepatic cells.22
In our cohort of patients with chronic HCV, there was a striking correlation between TNF‐α and SOCS‐3 mRNA levels, consistent with a role for this cytokine in induction of SOCS‐3 expression in vivo.
Importantly, expression of SOCS‐3 in the liver is induced by cytokines and hormones that are associated with obesity dependent insulin resistance.39
Upregulation of hepatic SOCS‐1 and ‐3 mRNA and proteins has been observed in various insulin resistant animal models.26
A marked decrease in SOCS‐3 expression was found in obese mice lacking TNF‐α signalling, supporting the premise that elevated levels of SOCS‐3 in obesity may be related to increased TNF‐α expression.40
In our study, obese subjects with viral genotype 1 had increased hepatic expression of PEPCK compared with non‐obese subjects, consistent with impaired hepatocyte insulin sensitivity. PEPCK catalyses a key step in gluconeogenesis and insulin decreases the transcription of its gene.41
Insulin resistance is associated with failure of insulin to suppress the activity of enzymes involved in gluconeogenesis leading to increased hepatic glucose production.42
In our cohort of subjects with chronic HCV, highly significant correlations were seen between hepatic PEPCK and both TNF‐α and SOCS‐3 mRNA levels. Similar to their inhibitory role in IFN‐α signalling, TNF‐α and SOCS‐3 may act as negative regulators in insulin signalling.25
In our patients infected with viral genotype 3, there was no statistically significant difference in markers of insulin resistance or hepatic gene expression of PEPCK, SOCS‐3, or TNF‐α between obese and non‐obese patients. It remains unclear why the effect of obesity on hepatic insulin resistance and expression of SOCS‐3 was seen in subjects with viral genotype 1 but not genotype 3. The prevalence of cirrhosis was higher in the cohort of subjects infected with viral genotypes 1 or 4, and this may have contributed to an overall increase in insulin resistance in this population. However, the relationships between obesity and expression of PEPCK, SOCS‐3, or TNF‐α were found to be independent of the presence of cirrhosis. Interestingly, a previous study has also shown that subjects with genotype 3 have lower levels of insulin resistance compared with other viral genotypes.43
In addition, the increased risk for the development of type 2 diabetes in chronic HCV appears to be largely among non‐genotype 3 infected subjects.43,44,45
In contrast with the effect of obesity on hepatic gene expression, no differences in mRNA levels studied were seen between subjects with or without hepatic steatosis.
A number of earlier studies demonstrated that a sustained response to antiviral therapy is dependent on high levels of expression of the IFN‐α receptor.46,47
Information regarding the regulation of expression of the interferon receptor in chronic HCV remains limited. In our study, we found no difference in expression of the IFN‐R1 between obese and non‐obese subjects. Although a previous study demonstrated downregulation of IFN‐R1 mRNA in fibrotic livers,48
we did not observe this finding in our subjects with chronic HCV.
In summary, in our cohort of patients with chronic HCV, BMI
was independently associated with non‐response to antiviral therapy. In subjects with viral genotype 1, obesity was associated with increased PEPCK mRNA levels, consistent with impaired hepatocyte insulin sensitivity, and with increased expression of TNF‐α and SOCS‐3, factors that may reduce interferon signalling. Induction of hepatic SOCS‐3 expression may be one mechanism by which obesity reduces the biological response to IFN‐α in patients infected with viral genotype 1.