Silibinin ameliorates steatosis and insulin resistance during non-alcoholic fatty liver disease development partly through targeting IRS-1/PI3K/Akt pathway

Zhang, Yongxiang; Hai, Jian; Cao, Meng; Zhang, Yongli; Pei, Sujuan; Wang, Junbo; Zhang, Qinggui

doi:10.1016/j.intimp.2013.08.019

Cited by 80 publications

(65 citation statements)

References 33 publications

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“…The results suggested that silymarin could effectively inhibit the HFD-induced fatty liver and improve the liver function. Our results are in agreement with data obtained with a rat model (Zhang et al 2013).…”

Section: Discussionsupporting

confidence: 93%

Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice

Guo

Wang

et al. 2016

Pharmaceutical Biology

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Context: Silymarin is the main flavonoid extracted from milk thistle, which has been used to treat liver diseases. Objective: The in vivo effect of silymarin on HFD-induced insulin resistance and fatty liver in mice was studied. Materials and methods: Male C57BL/6 mice were fed with high-fat diet (HFD) to induce obesity and insulin resistance and treated with 30, 60 mg/kg silymarin for 18 days. Food intake, body weight and the content/histology of epididymal fat and liver tissue were examined; the content of lipids, AST, ALT and inflammatory cytokines in serum were estimated. Results: Administration of silymarin caused bodyweight loss in diet induced obesity (DIO) mice (HFD group: 47.7 g, 60 mg/kg group: 43.0 g) while the food intake remain unchanged. Silymarin (60 mg/kg) significantly reduced the epididymal fat mass (from 1.75 g to 1.12 g). Elevated plasma lipids (TC 6.1 mM, TG 1.3 mM, LDL 1.2 mM) in DIO mice were all suppressed by silymarin (TC 4.5 mM, TG 0.89 mM, LDL 0.9 mM), as well as insulin (5.1 ng/ml in HFD group to 2.0 ng/ml (60 mg/kg silymarin). Examination of cytokine levels (TNF-a, IL-1b and IL-6) in each group proved that silymarin treatment significantly decreased inflammation in DIO mice. Finally, silymarin effectively protected liver from HFD-induced injury as evidenced by decreasing histological damage and reducing ALT and AST levels, as follows: ALT; 47.4 U/L in HFD group to 28.4 U/L (60 mg/kg silymarin); AST; 150.1 U/L in HFD group to 88.1 U/L (60 mg/kg silymarin) in serum. Discussion and conclusion: Our results suggested that silymarin-induced alleviation of inflammatory response could be a mechanism responsible for its benefits against liver damage and insulin resistance. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 93%

Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice

Guo

Wang

et al. 2016

Pharmaceutical Biology

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“…In consistency with this, García-Maceira and Mateo (17) showed that silybin inhibited human cervical cancer as well as hepatoma cells through the PI3K/Akt/mTOR signaling pathway. Zhang et al (18) reported that silybin ameliorated steatosis and insulin resistance during non-alcoholic fatty liver disease development via the PI3K/Akt pathway. The results of the present study indicated that silybin significantly reduced PI3K and p-Akt protein levels in U266 cells in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

Feng

Luo

Guo

2016

Molecular Medicine Reports

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Abstract. Silybin is a biologically active component extracted from the seeds of Silybum marianum, which has been shown to have inhibitory effects on prostate, skin, bladder, lung and colon cancer cells, in addition to its efficacy in the treatment of liver diseases, including hepatitis and cirrhosis. The aim of the present study was to investigate whether silybin suppresses the proliferation and induces apoptosis of multiple myeloma (MM) cells and to elucidate its molecular targets. The proliferative and apoptotic rates of the U266 MM cell line were assessed using MTT and flow-cytometric assays, respectively. Western blot analysis was used to assess the protein levels of phosphoinositide-3 kinase (PI3K), phosphorylated (p)-Akt and p-mammalian target of rapamycin (mTOR) in U266 cells. In addition, PI3K inhibitor LY294002 or activator insulin-like growth factor 1 were used to investigate the involvement of the PI3K/Akt-mTOR signaling pathway in the effect of silybin on U266 cells. The results revealed that silybin restrained the proliferation and enhanced the apoptosis of U266 cells. Furthermore, silybin inhibited the protein expression of PI3K, p-Akt and p-mTOR in U266 cells. Of note, inhibition of PI3K facilitated silybin-mediated reduction of mTOR activation, cell proliferation and induction of apoptosis in U266 cells, while activation of PI3K attenuated the effects of silybin. In conclusion, silybin suppressed cell proliferation and promoted apoptosis of U266 cells via PI3K/Akt-mTOR signaling pathways.

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“…For example, hepatic fat accumulation in rats with high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) was accompanied with reduced phosphorylation of Akt, and pharmacological inhibitor of Akt led to significant fat accumulation in rat liver [13]. Some other studies demonstrated that Akt activation could ameliorate hepatic steatosis in lean mice, ob/ob mice, NAFLD mice, and diabetic mice [14], [15], [16]. Results of these studies clearly demonstrate that Akt plays important roles in regulating the lipid homeostasis in the liver.…”

Section: Introductionmentioning

confidence: 99%

Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver

et al. 2018

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Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.

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Silibinin ameliorates steatosis and insulin resistance during non-alcoholic fatty liver disease development partly through targeting IRS-1/PI3K/Akt pathway

Cited by 80 publications

References 33 publications

Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice

Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver

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