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

Publication ,  Journal Article
Younossi, ZM; Stepanova, M; Estep, M; Negro, F; Clark, PJ; Hunt, S; Song, Q; Paulson, M; Stamm, LM; Brainard, DM; Subramanian, GM; Patel, K ...
Published in: J Hepatol
January 2016

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, 4weeks 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.

Duke Scholars

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

January 2016

Volume

64

Issue

1

Start / End Page

29 / 36

Location

Netherlands

Related Subject Headings

  • Sofosbuvir
  • Ribavirin
  • Recurrence
  • Middle Aged
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatitis C, Chronic
  • Hepacivirus
  • Genotype
 

Citation

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MLA
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Younossi, Z. M., Stepanova, M., Estep, M., Negro, F., Clark, P. J., Hunt, S., … Patel, K. (2016). Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin. J Hepatol, 64(1), 29–36. https://doi.org/10.1016/j.jhep.2015.08.027
Younossi, Zobair M., Maria Stepanova, Michael Estep, Francesco Negro, Paul J. Clark, Sharon Hunt, Qinghua Song, et al. “Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin.J Hepatol 64, no. 1 (January 2016): 29–36. https://doi.org/10.1016/j.jhep.2015.08.027.
Younossi, Zobair M., et al. “Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin.J Hepatol, vol. 64, no. 1, Jan. 2016, pp. 29–36. Pubmed, doi:10.1016/j.jhep.2015.08.027.
Younossi ZM, Stepanova M, Estep M, Negro F, Clark PJ, Hunt S, Song Q, Paulson M, Stamm LM, Brainard DM, Subramanian GM, McHutchison JG, Patel K. Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin. J Hepatol. 2016 Jan;64(1):29–36.
Journal cover image

Published In

J Hepatol

DOI

EISSN

1600-0641

Publication Date

January 2016

Volume

64

Issue

1

Start / End Page

29 / 36

Location

Netherlands

Related Subject Headings

  • Sofosbuvir
  • Ribavirin
  • Recurrence
  • Middle Aged
  • Male
  • Liver Cirrhosis
  • Humans
  • Hepatitis C, Chronic
  • Hepacivirus
  • Genotype