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Oxaliplatin aggravates hepatic oxidative stress, inflammation and fibrosis in a non‑alcoholic fatty liver disease mouse model.

ABSTRACT: Oxaliplatin (OXA)‑based chemotherapy is widely used in the treatment of gastrointestinal tumors; however, it is associated with chemotherapy‑associated liver injury. Whether OXA induces liver injury and aggravates the already existing hepatic oxidative stress, inflammation and fibrosis in non‑alcoholic fatty liver disease (NAFLD), and whether these effects can be alleviated by reduced glutathione (GSH) treatment, remains unclear. In the present study, OXA induced acute liver injury in NAFLD mice. Moreover, OXA increased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased the levels of superoxide dismutase and GSH peroxidase in the livers of NAFLD mice. OXA also induced the upregulation of hepatic inflammatory cytokines, such as tumor necrosis factor (TNF)‑α, interferon (IFN)‑γ and interleukin (IL)‑17, in NAFLD mice. Furthermore, collagen fiber deposition in liver tissues was increased and the expression of transforming growth factor (TGF)‑β, α‑smooth muscle actin (SMA) and tissue inhibitor of metallopeptidase (TIMP)‑1 was upregulated in the livers of OXA‑treated NAFLD mice. Treatment with exogenous GSH alleviated OXA‑induced acute liver injury in NAFLD mice, and significantly reduced the levels of ROS, MDA and TNF‑α. However, GSH treatment did not inhibit collagen fiber deposition, although it reduced the levels of IFN‑γ, IL‑17, TGF‑β, α‑SMA and TIMP‑1 in the livers of OXA‑treated NAFLD mice. In conclusion, OXA chemotherapy may induce acute liver injury and aggravate the existing hepatic oxidative stress, inflammation and fibrosis in NAFLD. Treatment of NAFLD mice with exogenous GSH alleviated OXA‑induced liver injury, possibly by ameliorating OXA‑aggravated hepatic oxidative stress and inflammation; it did not, however, attenuate OXA‑aggravated liver fibrosis.

SUBMITTER: Lu Y

PROVIDER: S-EPMC6488186 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Oxaliplatin aggravates hepatic oxidative stress, inflammation and fibrosis in a non‑alcoholic fatty liver disease mouse model.

Lu Yulei Y Lin Youzhi Y Huang Xiaoqing X Wu Shengming S Wei Jian J Yang Chun C

International journal of molecular medicine 20190401 6

Oxaliplatin (OXA)‑based chemotherapy is widely used in the treatment of gastrointestinal tumors; however, it is associated with chemotherapy‑associated liver injury. Whether OXA induces liver injury and aggravates the already existing hepatic oxidative stress, inflammation and fibrosis in non‑alcoholic fatty liver disease (NAFLD), and whether these effects can be alleviated by reduced glutathione (GSH) treatment, remains unclear. In the present study, OXA induced acute liver injury in NAFLD mice ...[more]

PMID: 30942432

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Project description:Background & aimsDespite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD.MethodsUsing modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4).ResultsThe AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified.ConclusionsSerum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Clinical trial numberNot applicable.Impact and implicationsAn aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.

Dataset Information

Oxaliplatin aggravates hepatic oxidative stress, inflammation and fibrosis in a non‑alcoholic fatty liver disease mouse model.

Publications

Oxaliplatin aggravates hepatic oxidative stress, inflammation and fibrosis in a non‑alcoholic fatty liver disease mouse model.

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