Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet‐induced mouse model of nonalcoholic fatty liver disease

Pisonero-Vaquero, Sandra; Martínez-Ferreras, Ángel; García‐Mediavilla, María Victoria; Martínez‐Flórez, Susana; Fernández, Anna; Benet, Marta; Olcoz, J.L.; Jover, Ramiro; González‐Gallego, Javier; Sánchez-Campos, Sonia

doi:10.1002/mnfr.201400913

Cited by 113 publications

(79 citation statements)

References 67 publications

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“…Additionally, FABP1 repression was associated to the impaired expression of transcription factors FOXA1 and C/EBP, contributing to exacerbate lipotoxicity and lipid accumulation in NAFLD [35]. Our results also confirm previous observations showing that quercetin treatment attenuated FABP1 downregulation through the modulation of their major regulatory transcription factors in different models of NAFLD [5]. Moreover, findings support the capacity of quercetin to reduce FAT/CD36 upregulation associated with insulin resistance and steatosis, as previously observed in several nutritional models of NAFLD [5,32].…”

Section: Discussionsupporting

confidence: 91%

“…In spite of the role of de novo lipogenesis deregulation, fatty acid uptake seems to play a key implication in the pathogenesis of NAFLD [5,22,32,35]. In the present study, quercetin treatment modulated the impaired gene expression of several fatty acid uptake-and trafficking-related proteins.…”

Section: Discussionmentioning

confidence: 48%

“…Oral supplementation with quercetin in HFD-fed mice counteracts increased liver weight by reducing liver steatosis derived from a disminished plasma dyslipidemia and hepatic triglyceride accumulation, supporting the protective effect of quercetin on metabolic biomarkers in experimentally induced NAFLD [5,30,31].…”

Section: Discussionmentioning

confidence: 70%

“…Thus, in the current study LXR and its downstream lipogenic genes were overexpressed in HFD-fed mice. LXR plays a role as a contributing factor for NAFLD-related steatosis development by enhancing lipogenesis in in vivo and in vitro models and in the liver of patients [5,34]. This transcription factor increases fatty acid synthesis by either upregulating SREBP-1c or directly binding to the promoters of lipogenic genes, including fatty acid synthase [34].…”

Section: Discussionmentioning

confidence: 99%

“…The "multiple hit" hypothesis conceives a complex interplay between multiple events acting in parallel with genetic predisposition, providing a more accurate explanation of the pathogenic mechanisms involved in NAFLD. Thus, NAFLD development and progression depend on changes in lipid metabolism, derived from the induction of fatty acid biosynthesis and transport that contributes to the intrahepatic lipid accumulation associated with insulin resistance, accompanied by oxidative stressmediated lipotoxicity and proinflammatory cytokines gene expression, among others mechanisms [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

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Nistal

Martínez‐Flórez

et al. 2017

Free Radical Biology and Medicine

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Abbreviations: ALT, alanine aminotransferase; C/EBPα, CCAAT/enhancer binding protein alpha; CHOP, CCAAT-enhancer-binding protein homologous protein; CYP2E1, cytochrome P450 2E1; DAMPs, danger-associated molecular patterns; FABP1, fatty acid binding protein 1; FAS, fatty acid synthase; FAT/CD36, fatty acid translocase CD36; FFA, free fatty acid; FOXA1, forkhead box protein A1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRP78, 78 kDa glucose-regulated protein; HFD, high fat diet; HOMA-IR, homeostasis model assessment of insulin resistance; IAP, intestinal phosphatase alkaline; IL-6, interleukin 6; LPO, lipid peroxidation; LPS, lipopolysaccharide; LXRα, liver X receptor alpha; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NF-B , nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3;PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors; SCFAs, short-chain fatty acids; SREBP-1c, sterol regulatory element binding protein 1c; TG, triglycerides; TLR, Toll-like receptor; TNF-αtumor necrosis factor; UPR, unfolded protein response. AbstractGut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

Porras

Nistal

Martínez‐Flórez

et al. 2017

Free Radical Biology and Medicine

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412

259

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Pure total flavonoids from citrus improve nonalcoholic steatohepatitis liver inflammatory responses by regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway

et al. 2022

The Anatomical Record

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Background and AimNonalcoholic steatohepatitis (NASH) is a critical stage in the prognosis of nonalcoholic fatty liver disease (NAFLD). Pure total flavonoids from circus (PTFC) play essential roles in the improvement of NASH symptoms, but the underlying regulatory mechanism remains elusive. Our previous high‐throughput omics screening results indicate that the CCL2/CCR2‐PI3K‐Akt signaling pathway is a key pathway that regulates the liver inflammatory response. PTFC may regulate the CCL2/CCR2‐PI3K‐Akt signaling pathway to improve the liver inflammatory response.MethodsA mice model of NASH was established by a high‐fat diet, and PTFC was used as treatment. Hematoxylin‐eosin and oil red O staining were used to observe the pathological changes in the liver tissue. Western blotting and real‐time PCR were used to measure the mRNA and protein levels in the liver. The expression of proinflammatory cytokines in the peripheral blood and liver tissues was measured by liquid suspension array. An automatic biochemical method was used to examine serum transaminases and lipids levels, as well as liver lipids.ResultsCompared with the mice in the high‐fat diet group, mice in the HFD + PTFC group showed significantly improved liver histopathology, and levels of serum transaminase and lipids, liver lipids and serum proinflammatory cytokines. Moreover, the mRNA and protein expression and phosphorylation levels of key signaling molecules in the CCL2/CCR2‐PI3K‐Akt signal transduction pathway were obviously reduced by PTFC treatment.Conclusive RemarksPTFC can ameliorate NASH symptoms, and the mechanism may be related to regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway to reduce the liver inflammatory response.

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Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

et al. 2018

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This study was conducted to screen flavonoids for affecting expression of desaturases involved in omega-3 fatty acid synthesis and ceramide (CER) metabolism. To this end, cultured HepG2 hepatocytes, C2C12 myocytes, and 3T3-L1 adipocytes were treated with nontoxic concentrations of 12 selected flavonoids and expression of Δ4-, Δ5-, and Δ6-desaturases (DEGS1, FADS1, and FADS2, respectively) was determined. The flavonoids tested were more cytotoxic to HepG2 and 3T3-L1 than to C2C12 cells. In HepG2 cells, FADS1 was induced by quercetin and FADS2 expression was increased by daidzein, genistein, and pratensein treatment. DEGS1 was increased by apigenin, luteolin, orobol, and quercetin administration. In differentiated C2C12 cells, substances had no inducing effect or even lowered target gene expression. Pratensein induced both FADS1 and FADS2 in differentiated 3T3-L1 cells and DEGS1 was increased by treatment with apigenin, genistein, luteolin, orobol, and quercetin. In conclusion, pratensein may be an interesting test compound for further studies in vitro and in vivo on omega-3 synthesis since it induces its rate-limiting enzyme FADS2. Apigenin, luteolin, orobol, and quercetin induced DEGS1 and thereby possibly synthesis of proapoptotic CER in malignant HepG2 cells and 3T3-L1. In contrast, in benign C2C12 cells, they did not elevate mRNA steady state levels of DEGS1. That may partly explain the higher resistance of C2C12 cells against flavonoids compared to the other cell lines. By affecting tumor cells and nontumor cells differently, these flavonoids may be promising substances for further research regarding anticancer properties. © 2018 BioFactors, 44(5): [485][486][487][488][489][490][491][492][493][494][495] 2018

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Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet‐induced mouse model of nonalcoholic fatty liver disease

Abstract: Conclusion:These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.

Cited by 113 publications

References 67 publications

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

Pure total flavonoids from citrus improve nonalcoholic steatohepatitis liver inflammatory responses by regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway

Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

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