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Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome

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Abstract

Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.

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Abbreviations

HCV:

Hepatitis C virus

IR:

Insulin resistance

PEPCK:

Phosphoenol enol pyruvate carboxykinase

G6P:

Glucose-6-phosphatase

CREB:

cAMP responsive element binding protein

T2DM:

Type 2 diabetes mellitus

IRS:

Insulin receptor substrate

PGC:

Peroxisome proliferator-activated receptor gamma coactivator

DGAT:

Diacylglycerol acyltransferase

MTP:

Microsomal triglyceride transfer protein

PPARγ:

Peroxisome proliferator-activated receptor-gamma

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Acknowledgments

We are thankful to Dr. Takaji Wakita (NIID, Tokyo, Japan) and Dr. Charles Rice (Rockfeller University, USA) for the generous gift of HCV genotype 2a (JFH-1) and the Huh7.5 cell line to Dr. Gulam Waris at Rosalind Franklin University of Medicine & Science (RFUMS), USA. Financial support of the Higher Education Commission of Pakistan (HEC) is highly acknowledged.

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The authors declare that they have no competing interests.

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Correspondence to Sobia Manzoor.

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Parvaiz, F., Manzoor, S., Iqbal, J. et al. Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome. Arch Virol 159, 1017–1025 (2014). https://doi.org/10.1007/s00705-013-1892-3

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