Potential involvement of PPAR α activation in diminishing the hepatoprotective effect of fenofibrate in NAFLD

Hamed, Asmaa M.; El-Kharashi, Omnyah A.; Boctor, Suzi S.A.; Abd-Elaziz, Lobna F.

doi:10.1016/j.biopha.2016.11.114

Cited by 20 publications

(9 citation statements)

References 49 publications

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“…Studies ( 24 ) have confirmed that the phosphorylated protein PPAR-α can enhance the body's sensitivity to insulin, inhibit the production of inflammatory factors and inflammation and inhibit the oxidative stress response; and its decreased expression can aggravate the inflammation and oxidative stress injury ( 25 ). It has been reported in literature ( 26 ) that CYP2E1 can inhibit the expression of PPAR-α. Therefore, it is speculated that EP can negatively regulate the CYP2E1-PPAR-α signaling pathway, thereby alleviating the oxidative stress and inflammatory injury.…”

Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

et al. 2018

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The effects of ethyl pyruvate (EP) on alcoholic liver disease and its related mechanism were investigated. Thirty male C57/BL6 mice were randomly divided to three groups: Control (n=10), alcoholic liver disease (ALD, n=10) and ethyl pyruvate group (EP, n=10). EP group was treated with gavage using EP (100 mg/kg) for 15 consecutive days. Control and ALD group were treated with the same volume of normal saline. After the last gavage, EP and ALD group were treated with the intraperitoneal injection of 50% alcoholic solution (10 ml/kg). After that, ALD and EP group received the gavage using alcohol for 4 weeks, while Control group received the same volume of normal saline, and blood and liver tissues were taken for detection. Results showed that in this experimental study that EP could effectively alleviate the alcoholic liver disease. The levels of alanine aminotransferase (AST), triglycerides (TG), free fatty acid (FFA) and FBG in EP group were significantly lower than those in ALD group, but the number of platelets was reversed, and the differences were statistically significant; the levels of anti-inflammatory factors (TGF-β/IL-10) and superoxide dismutase (SOD) in EP were significantly higher than those in ALP group, but the levels of pro-inflammatory factors (IL-6/TNF-α) and MDA were significantly lower than those in ALP group. EP upregulated CYP2E1, downregulated PPAR-α, nuclear factor 2 (Nrf2) and very-low density lipoprotein receptor (VLDLR), positively regulated the CYP2E1-PPAR-α-ROS signaling pathway and negatively regulated the ROS-Nrf2-VLDLR signaling pathway. EP can increase anti-inflammatory factors and decrease pro-inflammatory factors, enhance the activity of SOD and reduce FFA and TG. Moreover, it can upregulate the PPAR-α expression by negative regulation of CYP2E1-PPAR-α signaling pathway and downregulate the Nrf2 expression by negative regulation of Nrf2-VLDLR signaling pathway, thus alleviating the alcoholic liver disease.

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Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

et al. 2018

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“…NAFLD physiopathology-associated pathways were significantly enriched with NAFLD-regulated genes. Among these pathways, activation of PPAR and Hh signaling pathways is of special interest because their deregulation contributes to liver damage and metabolic syndrome [ 22 – 27 ]. Hh signaling is significantly upregulated in NASH, compared with the normal healthy liver [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

LingguizhuganDecoction Protects against High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease by Alleviating Oxidative Stress and Activating Cholesterol Secretion

Yang

Lin

Nugent

et al. 2017

International Journal of Genomics

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Background Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of liver transplantation. Lingguizhugan decoction (LGZG), a classical Chinese herbal formula, has beneficial effects on NAFLD animal models. Our study examined the impact of LGZG on hepatic global transcriptome of high-fat-diet-induced NAFLD rats. Methods Three groups of Wistar rats were included: normal, NAFLD model, and LGZG-treated NAFLD groups. Four weeks for the treatment, liver tissues were harvested for RNA sequencing. Differentially expressed genes (DEGs) and enriched pathways were detected on hepatic global transcriptome profile. Real-time PCR validated the regulatory patterns of LGZG on NAFLD rats. Results DEGs between the NAFLD model and normal groups indicated the elevated peroxisome proliferator-activated receptor (PPAR) and hedgehog signaling pathways in NAFLD rats. In bile secretion pathway, genes involved in cholesterol secretion were activated by LGZG treatment. Increased expression of antioxidant OSIGN1 and decreased expression of genes (AHR, IRF2BP2, and RASGEF1B) that induce oxidative stress and inflammation were observed in NAFLD rats treated with LGZG. The regulatory patterns of LGZG treatment on these oxidative stress-related genes were confirmed by real-time PCR. Conclusion Our study revealed a “two-hits-targeting” mechanism of LGZG in the treatment for NAFLD: alleviating oxidative stress and activating cholesterol secretion.

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“… 23 The mechanisms of the anti-hepatic fibrosis effect of traditional Chinese medicines involve multiple aspects, levels, and targets in the pathophysiological process of liver fibrosis and, therefore, show unique advantages. 24 The results of this study indicate that compared with the control group, the expression levels of collagen-I, collagen-III, and α-SMA in the liver tissues of the TAA-induced liver fibrosis rat model increased, and the collagen deposition was obvious and the degree of fibrosis increased. Activation of hepatic stellate cells (HSCs) is a central event in the development of hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 62%

Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats

Cao¹,

Zheng²,

Chen³

et al. 2018

DDDT

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PurposeThere is no effective treatment for liver fibrosis, which is a common phase during the progression of many chronic liver diseases to cirrhosis. Previous studies found that Semen Brassicae therapy can effectively improve the clinical symptoms of patients with asthma, allergic rhinitis, and chronic lung diseases; however, its effects on liver fibrosis in rats and its possible mechanisms of action remain unclear.MethodsRats were injected intraperitoneally with 4% thioacetamide aqueous solution (5 mL·kg−1) at a dose of 200 mg·kg−1 twice a week for 8 consecutive weeks to establish the liver fibrosis model and were then treated with different concentrations of Semen Brassicae extract. After Semen Brassicae treatment, the morphology of the liver tissue was analyzed using hematoxylin and eosin and Masson’s trichrome staining, and liver index and liver fibrosis grade were calculated. Thereafter, the levels of collagen-I, collagen-III, α-SMA, transforming growth factor (TGF)-β1, p-Smad 2/3, Smad 2/3, Smad4, NF-κB-p65, p-NF-κB-p65, IL-1β, IL-6, AKT, and p-AKT were determined using Western blotting.ResultsCompared with the untreated model group, the Semen Brassicae-treated group showed significantly decreased liver function indices; expression levels of collagen-I, collagen-III, and α-SMA; and hepatic fibrosis. Further studies also showed that the expression of TGF-β1, Smad4, p-Smad 2/3/Smad 2/3, p-NF-κB-p65/NF-κB-p65, IL-1β, IL-6, and p-AKT/AKT significantly decreased after the treatment.ConclusionThese results indicate that Semen Brassicae exhibits an anti-hepatic fibrosis effect, and the underlying mechanism of action may be related to the regulation of TGF-β1/Smad, NF-κB, and AKT signaling pathways and the reduction of extracellular matrix deposition.

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Potential involvement of PPAR α activation in diminishing the hepatoprotective effect of fenofibrate in NAFLD

Cited by 20 publications

References 49 publications

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

LingguizhuganDecoction Protects against High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease by Alleviating Oxidative Stress and Activating Cholesterol Secretion

Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats

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Potential involvement of PPAR α activation in diminishing the hepatoprotective effect of fenofibrate in NAFLD

Cited by 20 publications

References 49 publications

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway

LingguizhuganDecoction Protects against High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease by Alleviating Oxidative Stress and Activating Cholesterol Secretion

Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-&beta;1/Smad, nuclear factor-&kappa;B, and AKT signaling pathways in rats

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Semen Brassicae ameliorates hepatic fibrosis by regulating transforming growth factor-β1/Smad, nuclear factor-κB, and AKT signaling pathways in rats