TY - JOUR
T1 - Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin
AU - Younossi, Zobair M.
AU - Stepanova, Maria
AU - Estep, Michael
AU - Negro, Francesco
AU - Clark, Paul J.
AU - Hunt, Sharon
AU - Song, Qinghua
AU - Paulson, Matthew
AU - Stamm, Luisa M.
AU - Brainard, Diana M.
AU - Subramanian, G. Mani
AU - McHutchison, John G.
AU - Patel, Keyur
N1 - Funding Information:
This study was funded by Gilead Sciences, Inc. , United States of America.
Funding Information:
ZMY, FN, PC and KP have received research funding from Gilead Sciences, Inc. QS, MP, LS, DB, MS2, and JGM are employees of Gilead Sciences, Inc. MS1, ME, and SH have no conflict of interest.
Publisher Copyright:
© 2015 European Association for the Study of the Liver.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - HCV
KW - Lipid metabolism
KW - Ribavirin
KW - Sofosbuvir
UR - http://www.scopus.com/inward/record.url?scp=84953277716&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84953277716&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2015.08.027
DO - 10.1016/j.jhep.2015.08.027
M3 - Article
C2 - 26341824
AN - SCOPUS:84953277716
SN - 0168-8278
VL - 64
SP - 29
EP - 36
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -