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Metabolomics profiling to investigate the pharmacologic mechanisms of berberine for the treatment of high-fat diet-induced nonalcoholic steatohepatitis.

ABSTRACT: Objective. Berberine has been used to treat nonalcoholic steatohepatitis (NASH), which has been addressed in many studies. In this study, we investigated the molecular pharmacology mechanisms of berberine using metabolomic techniques. Methods. Sprague-Dawley rats were randomly divided into three groups (10 rats in each group): (i) normal control group; (ii) high-fat diet- (HFD-) induced NASH model group; and (iii) HFD berberine-treated group (i.d. 200?mg/kg). The handling procedure lasted eight weeks. Then, UPLC-Q-TOF/MS techniques coupled with histopathology and biochemical analyses were adopted to explore the mechanisms of berberine on the protective effects against NASH. Key Findings. (i) According to conventional test results, berberine treatment plays a fighting role in HFD-induced NASH due to its beneficial effects against insulin resistance, inflammation, and lipid metabolism. (ii) Based on UPLC-Q-TOF/MS techniques, metabolic profiles that involved sphingomyelin (SM), phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC), 13-hydroperoxy-9, 11-octadecadienoic acid (13-HpODE), eicosatrienoic acid, docosatrienoic acid, and eicosenoic acid could provide potential metabolic biomarkers to address the pharmacological mechanisms of berberine. Conclusions. The parts of molecular pharmacological mechanisms of berberine for NASH treatment are related to the regulation of metabolic disruption involving phospholipid and unsaturated fatty acids in rats with NASH.

SUBMITTER: Li J

PROVIDER: S-EPMC4421035 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Metabolomics profiling to investigate the pharmacologic mechanisms of berberine for the treatment of high-fat diet-induced nonalcoholic steatohepatitis.

Li Jian J Liu Zezhou Z Guo Mingxing M Xu Kejia K Jiang Miao M Lu Aiping A Gao Xiaoyan X

Evidence-based complementary and alternative medicine : eCAM 20150422

Objective. Berberine has been used to treat nonalcoholic steatohepatitis (NASH), which has been addressed in many studies. In this study, we investigated the molecular pharmacology mechanisms of berberine using metabolomic techniques. Methods. Sprague-Dawley rats were randomly divided into three groups (10 rats in each group): (i) normal control group; (ii) high-fat diet- (HFD-) induced NASH model group; and (iii) HFD berberine-treated group (i.d. 200 mg/kg). The handling procedure lasted eight ...[more]

PMID: 25977701

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Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

Project description:Nonalcoholic fatty liver disease (NAFLD) is the most frequent histological finding in individuals with abnormal liver-function tests in the Western countries. In previous studies, we have shown that oxidative phosphorylation (OXPHOS) is decreased in individuals with NAFLD, but the cause of this mitochondrial dysfunction remains uncertain. The aims of this study were to determine whether feeding mice a high-fat diet (HFD) induces any change in the activity of OXPHOS, and to investigate the mechanisms involved in the pathogenesis of this defect. To that end, 30 mice were distributed between five groups: control mice fed a standard diet, and mice on a HFD and treated with saline solution, melatonin (an antioxidant), MnTBAP (a superoxide dismutase analog) or uric acid (a scavenger of peroxynitrite) for 28 weeks intraperitoneously. In the liver of these mice, we studied histology, activity and assembly of OXPHOS complexes, levels of subunits of these complexes, gene expression of these subunits, oxidative and nitrosative stress, and oxidative DNA damage. In HFD-fed mice, we found nonalcoholic steatohepatitis, increased gene expression of TNFα, IFNγ, MCP-1, caspase-3, TGFβ1 and collagen α1(I), and increased levels of 3-tyrosine nitrated proteins. The activity and assembly of all OXPHOS complexes was decreased to about 50-60%. The amount of all studied OXPHOS subunits was markedly decreased, particularly the mitochondrial-DNA-encoded subunits. Gene expression of mitochondrial-DNA-encoded subunits was decreased to about 60% of control. There was oxidative damage to mitochondrial DNA but not to genomic DNA. Treatment of HFD-fed mice with melatonin, MnTBAP or uric acid prevented all changes observed in untreated HFD-fed mice. We conclude that a HFD decreased OXPHOS enzymatic activity owing to a decreased amount of fully assembled complexes caused by a reduced synthesis of their subunits. Antioxidants and antiperoxynitrites prevented all of these changes, suggesting that nitro-oxidative stress played a key role in the pathogenesis of these alterations. Treatment with these agents might prevent the development of NAFLD in humans.

Dataset Information

Metabolomics profiling to investigate the pharmacologic mechanisms of berberine for the treatment of high-fat diet-induced nonalcoholic steatohepatitis.

Publications

Metabolomics profiling to investigate the pharmacologic mechanisms of berberine for the treatment of high-fat diet-induced nonalcoholic steatohepatitis.

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