Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin

Younossi, Zobair M., Stepanova, Maria, Estep, Michael, Negro, Francesco, Clark, Paul J., Hunt, Sharon, Song, Qinghua, Paulson, Matthew, Stamm, Luisa M., Brainard, Diana M., Subramanian, G. Mani, McHutchison, John G. and Patel, Keyur (2016) Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin. Journal of Hepatology, 64 1: 29-36. doi:10.1016/j.jhep.2015.08.027

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Author Younossi, Zobair M.
Stepanova, Maria
Estep, Michael
Negro, Francesco
Clark, Paul J.
Hunt, Sharon
Song, Qinghua
Paulson, Matthew
Stamm, Luisa M.
Brainard, Diana M.
Subramanian, G. Mani
McHutchison, John G.
Patel, Keyur
Title Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin
Journal name Journal of Hepatology   Check publisher's open access policy
ISSN 0168-8278
1600-0641
Publication date 2016-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.jhep.2015.08.027
Open Access Status File (Author Post-print)
Volume 64
Issue 1
Start page 29
End page 36
Total pages 8
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Language eng
Formatted abstract
Background & Aims: Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir + ribavirin.
Methods: Serum samples [baseline, treatment week 12, 4 weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform.
Results: We selected 127 patients (GT2 n = 50, GT3 n = 77), 50% cirrhotic patients, and 42% who experienced a virological relapse. At baseline, GT3 patients had lower level of serum lipids, apoB/E, 7-dehydrocholesterol, desmosterol, lathosterol, compared to GT2 (p <0.006). Baseline lathosterol was lower in relapsers with cirrhosis compared to cirrhotic patients with SVR (p = 0.003). From baseline to treatment week 12, serum lipids, apoB/E, and key sterol pathway metabolites (7-dehydrocholesterol, desmosterol, lathosterol, lanosterol) increased in GT3. In contrast, in GT2 patients, apoB/E and dihydrolanosterol decreased with viral suppression (p <0.025). At follow-up week 4, cirrhotic SVR patients showed substantially greater increases in apoB and total sterols compared to cirrhotic relapsers regardless of HCV genotype. After adjustment for genotype and gender, baseline lathosterol was independently associated with virologic response (p = 0.04).
Conclusion: HCV GT3 is associated with reduced circulation of lipids involved in the distal cholesterol biosynthesis pathway, resulting in relative hypocholesterolemia. HCV suppression during sofosbuvir + ribavirin restores distal sterol metabolites indicating viral interference with de novo lipogenesis or selective retention by hepatocytes.
Keyword HCV
Sofosbuvir
Ribavirin
Lipid metabolism
Hepatitis C virus
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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