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WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

ABSTRACT: The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

SUBMITTER: Gao YS

PROVIDER: S-EPMC7468331 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

Gao Ying-Sheng YS Qian Min-Yi MY Wei Qiang-Qiang QQ Duan Xu-Bin XB Wang Shi-Lei SL Hu Hai-Yang HY Liu Jun J Pan Chu-Yue CY Zhang Shuo-Quan SQ Qi Lian-Wen LW Zhou Jin-Pei JP Zhang Hui-Bin HB Wang Li-Rui LR

Acta pharmacologica Sinica 20191023 3

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymat ...[more]

PMID: 31645659

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Project description:Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH) are major metabolic diseases with increasing global prevalence and no approved therapies. There is a mounting need to develop biomarkers of diagnosis, prognosis and treatment response that can effectively replace current requirements for liver biopsies, which are invasive, error-prone and expensive. We performed SomaLogic serum proteome profiling with baseline (n = 231) and on-treatment (n = 72, Weeks 12 and 16, Placebo and 25 mg PF-05221304) samples from a Phase 2a trial (NCT03248882) with Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi) in patients with NAFLD/NASH. SomaSignal NASH probability scores and expression data for 7000+ analytes were analyzed to identify potential biomarkers associated with baseline clinical measures of NAFLD/NASH [Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] as well as biomarkers of treatment response to ACCi. SomaSignal NASH probability scores identified biopsy-proven/clinically defined NIT-based (Presumed) NASH classification of the cohort with > 70% agreement. Clesacostat-induced reduction in steatosis probability scores aligned with observed clinical reduction in hepatic steatosis based on MRI-PDFF. We identify a set of 69 analytes that robustly correlate with clinical measures of hepatic inflammation and steatosis (MRI-PDFF, ALT and AST), 27 of which were significantly reversed with ACC inhibition. Clesacostat treatment dramatically upregulated Wnt5a protein and Apolipoproteins C3 and E, with drug-induced changes significantly correlating to changes on MRI-PDFF. Our data demonstrate the utility of SomaLogic- analyte panel for diagnosis and treatment response in NAFLD/NASH and provide potential new mechanistic insights into liver steatosis reduction, inflammation and serum triglyceride elevation with ACC inhibition. (Clinical Trial Identifier: NCT03248882).

Project description:Background:Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by hepatic steatosis, lobular inflammation and fibrosis. Acetyl-CoA carboxylase (ACC) isoform 1 and 2 involved in de novo lipogenesis (DNL) and fatty acid oxidation have been identified as a therapeutic target in NASH. GS-0976, the inhibitor of ACC1 and ACC2, has achieved favorable therapeutic effects in clinical trials with NASH. The purpose of this study was to explore the transcriptional alterations regulated by GS-0976 in NASH. Methods:C57BL/6 mice were fed on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or normal diet for 12 weeks. Mice were treated with or without GS-0976 (3 mg/kg per day) in the last 8 weeks. Oil Red O, Haematoxylin-eosin (H & E), and Sirius Red were used to evaluate hepatic steatosis, inflammation and fibrosis. The comparative RNA-sequencing was conducted to analyse the hepatic gene expression profiles in mice. Reverse transcription-polymerase chain reaction analysis was performed to validate the differential expression of representative genes. Results:GS-0976 attenuated the steatosis, inflammation, and fibrosis of NASH in CDAHFD mouse model. High-throughput sequencing and differential gene expression analysis showed that there were 516 up-regulated genes and 525 down-regulated genes after GS-0976 treatment. Genes involved in the metabolic process, extracellular matrix formation, immune response, and angiogenesis were significantly enriched. The "Metabolic pathways" and "ECM-receptor interaction" pathways were the most significantly enriched KEGG pathways in the up-regulated and down-regulated differentially expressed genes (DEGs), respectively. Conclusions:Transcriptome analysis showed that GS-0976 could regulate the expression of genes related to metabolism, inflammation and fibrosis in NASH. The global transcriptomic changes in gene expression promote the further understanding for the inhibition mechanisms of GS-0976 in NASH.

Dataset Information

WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

Publications

WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

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