Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice

Diniz, Tiego Aparecido; Lima, Edson Alves de; Teixeira, Alexandre Abílio de Souza; Biondo, Luana Amorim; Rocha, Lucas Ariel Fernandes da; Valadão, Iuri Cordeiro; Silveira, Loreana Sanches; Cabral-Santos, Carol; Souza, Camila Oliveira de; Neto, José Cesar Rosa

doi:10.1016/j.lfs.2020.118868

Cited by 85 publications

(50 citation statements)

References 63 publications

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“…Activated Akt can further activate SREBP1c, 26 and inhibition of PPARα also promotes the development of MAFLD. 29,30 However, in the present study, offspring mice with HFD-induced MAFLD showed increased SREBP1c and PPARα expression, while MNE treatment significantly down-regulated the expression of both SREBP1c and PPARα. Both findings contradict previously reported data, indicating the mechanism by which MNE induced lipid metabolism disorder was different from that responsible for the development of HFDinduced MAFLD.…”

Section: Discussioncontrasting

confidence: 72%

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Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Huang

Chen

et al. 2021

Liver International

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Aim The aim of this study is to investigate the effect of maternal nicotine exposure (MNE) on the development of metabolic associated fatty liver disease (MAFLD) in adulthood offspring and the underlying mechanism. Methods Pregnant mice (n = 22) were subcutaneously injected with either saline vehicle (n = 11) or nicotine (n = 11) twice a day on gestational days 11‐21. Offspring mice (n = 176) from both groups were weaned at postnatal day 21, and for 6 months after postnatal day 21, 96 mice were fed either a standard chow diet (n = 48) or a high‐fat diet (n = 48). Serum lipid indicators, liver function indicators, insulin, and liver mitochondrial respiration were analyzed. The expression levels of fibrosis‐related proteins, phosphorylated PI3K, phosphorylated Akt, sterol regulatory element‐binding transcription factor 1 (SREBP1c), and peroxisome proliferator‐activated receptor alpha (PPAR‐α) were detected in the liver by immunohistochemistry and Western blotting. Results MNE significantly decreased the weight of both maternal and offspring mice (~30%) and inhibited organ growth in offspring mice (P < .05). MNE also significantly increased serum levels of total bile acid, triglycerides, total cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, low‐density lipoprotein, and insulin while decreasing serum high‐density lipoprotein levels and mitochondrial respiration activity in mice fed either the normal diet or high‐fat diet (all P < .05). These effects of MNE on lipid metabolism and insulin resistance were mediated via PI3K and Akt phosphorylation and down‐regulation of SREBP1c and PPAR‐α. Conclusion Our data indicate MNE induces lipid metabolism disorder and insulin resistance to promote MAFLD progression in adult offspring through activation of PI3K/Akt signaling and suppression of SREBP1c and PPARα protein expression.

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Section: Discussioncontrasting

confidence: 72%

“…Activated Akt can further activate SREBP1c, 26 and inhibition of PPARα also promotes the development of MAFLD 29,30 . However, in the present study, offspring mice with HFD‐induced MAFLD showed increased SREBP1c and PPARα expression, while MNE treatment significantly down‐regulated the expression of both SREBP1c and PPARα.…”

Section: Discussioncontrasting

confidence: 67%

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Huang

Chen

et al. 2021

Liver International

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“…Activation of AMPK is connected to improvement in liver inflammation and metabolism in NAFLD [ 54 , 55 ]. Additionally, several studies have demonstrated that AMPK signaling pathways are involved in liver steatosis and steatohepatitis [ 56 ]. Research in 2014 indicated that fenofibrate could modulate AMPK signaling and thereby exert its therapeutic effect [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Mahmoudi

Butler

Jamialahmadi

et al. 2021

BioMed Research International

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Background. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. Methods. We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. Results. We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Conclusion. Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.

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“…These results indicated that acetate enhanced FAO through modulating PPARα signaling. Several pieces of evidence verified that PPARα was the downstream target of AMPK [45]. Therefore, to explore whether activation of PPARα signaling was related to AMPK we firstly determined the effects of acetate and BAA6-CM on AMPK activity in 3T3-L1 cells.…”

Section: Pparα Signaling Mediated the Regulation Of Acetate On Fao In 3t3-l1 Cellsmentioning

confidence: 99%

Bifidobacterium animalis subsp. lactis A6 Enhances Fatty Acid β-Oxidation of Adipose Tissue to Ameliorate the Development of Obesity in Mice

Huo

Zhao

et al. 2022

Nutrients

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Fatty acid β-oxidation (FAO) is confirmed to be impaired in obesity, especially in adipose tissues. We previously proved that Bifidobacterium animalis subsp. lactis A6 (BAA6) had protective effects against diet-induced obesity. However, whether BAA6 enhances FAO to ameliorate the development of obesity has not been explored. After being fed with high-fat diet (HFD) for 9 weeks, male C57BL/6J mice were fed HFD or BAA6 for 8 weeks. In vitro study was carried out using 3T3-L1 adipocytes to determine the effect of BAA6 culture supernatant (BAA6-CM). Here, we showed that administration of BAA6 to mice fed with HFD decreased body weight gain (by 5.03 g) and significantly up-regulated FAO in epididymal adipose tissues. In parallel, FAO in 3T3-L1 cells was increased after BAA6-CM treatment. Acetate was identified as a constituent of BAA6-CM that showed a similar effect to BAA6-CM. Furthermore, acetate treatment activated the GPR43-PPARα signaling, thereby promoting FAO in 3T3-L1 cells. The levels of acetate were also elevated in serum and feces (by 1.92- and 2.27-fold) of HFD-fed mice following BAA6 administration. The expression levels of GPR43 and PPARα were increased by 55.45% and 69.84% after BAA6 supplement in the epididymal fat of mice. Together, these data reveal that BAA6 promotes FAO of adipose tissues through the GPR43-PPARα signaling, mainly by increasing acetate levels, leading to alleviating the development of obesity.

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Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice

Cited by 85 publications

References 63 publications

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Bifidobacterium animalis subsp. lactis A6 Enhances Fatty Acid β-Oxidation of Adipose Tissue to Ameliorate the Development of Obesity in Mice

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