Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin
| Autor: | Zobair M. Younossi, Matthew Paulson, Paul J. Clark, Maria Stepanova, Francesco Negro, Qinghua Song, John G. McHutchison, Luisa M. Stamm, Michael Estep, Diana M. Brainard, G. Mani Subramanian, Sharon L. Hunt, Keyur Patel |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Liver Cirrhosis Male 0301 basic medicine medicine.medical_specialty Genotype Sofosbuvir Apolipoprotein B Hepatitis C virus Blood lipids Lathosterol Hepacivirus ddc:616.07 medicine.disease_cause Antiviral Agents 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Recurrence Internal medicine Desmosterol Ribavirin medicine Humans Aged ddc:616 Hepatology biology Cholesterol virus diseases Hepatitis C Chronic Middle Aged medicine.disease Virology digestive system diseases Hypocholesterolemia Lipid metabolism 030104 developmental biology Endocrinology chemistry HCV biology.protein Drug Therapy Combination Female lipids (amino acids peptides and proteins) 030211 gastroenterology & hepatology medicine.drug |
| Zdroj: | Journal of Hepatology, Vol. 64, No 1 (2016) pp. 29-36 |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2015.08.027 |
| Popis: | 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.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.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 (p0.006). 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 (p0.025). 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).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. |
| Databáze: | OpenAIRE |
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