Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis

Hepatology Communications
Annie J KrugerRaymond T Chung

Abstract

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. We assessed the efficacy and durability of short and prolonged CVC therapy in a diet-induced mouse model of NASH, the choline deficient, L-amino acid-defined, high-fat diet (CDAHFD) model. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. CVC (10 mg/kg/day and 30 mg/kg/day for 4 weeks and 20 mg/kg/day and 30 mg/kg/day for 14 weeks) was initiated simultaneously with the CDAHFD. At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. High-dose CVC (30 mg/kg/day) therapy in CDAHFD mice for 4 or 14 weeks inhibited intrahepatic accumulation of Ly6Chigh bone marrow-derived macrophages. Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti-inflammatory macrophages in the high-dose CVC group. De...Continue Reading

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Citations

Sep 22, 2018·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Kenneth E ShermanShyam Kottilil
Dec 6, 2019·Hepatology International·Katharina C ReimerFrank Tacke
Jan 10, 2019·World Journal of Gastroenterology : WJG·Georgios Neokosmidis, Konstantinos Tziomalos
May 10, 2019·Frontiers in Immunology·Chris John WestonDavid H Adams
Jun 11, 2020·Clinical Diabetes and Endocrinology·Shaheen TomahOsama Hamdy
Jul 6, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Eunsol ChoiJang-Hoon Lee
Apr 20, 2021·Frontiers in Immunology·Arjuna Singanayagam, Evangelos Triantafyllou
Jul 8, 2021·Seminars in Cell & Developmental Biology·Emmanuel L GautierLaurent Yvan-Charvet
Nov 7, 2021·Nature Reviews. Immunology·Thierry Huby, Emmanuel L Gautier

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Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
dissecting

Clinical Trials Mentioned

NCT03028740

Software Mentioned

FACSDIVA
XPONENT
GraphPad
GraphPad Prism
FlowJo

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