title: Chronic administration of saturated fats and fructose differently affect SREBP activity resulting in different modulation of Nrf2 and Nlrp3 inflammasome pathways in mice liver.
abstract: The overconsumption of both saturated fats and fructose in the modern society has been related to the development of nonalcoholic fatty liver disease (NAFLD). However, the specific contribution of individual dietary components on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) has been poorly investigated. Therefore, the aim of our study was to investigate the dissimilar effects of these two dietary components on selected proinflammatory and antioxidant pathways in the liver of C57BL/6 mice fed a standard (SD), a 45% saturated fat (HFAT) or a 60% fructose (HFRT) diet for 12 weeks. HFAT diet evoked systemic metabolic alterations and overweight, not observed in HFRT mice. However, HFRT mice had a greater hepatic triglyceride deposition with increased ratio of triacylglycerols containing the palmitic acid compared to HFAT, as assessed by liquid chromatography-mass spectrometry analysis. This effect is due to the higher activation of the SCAP/SREBP1c lipogenic pathway by HFRT feeding. In addition, we found inhibition of Keap1/Nrf2 antioxidant signaling and more robust stimulation of the Nlrp3 inflammasome pathway in the livers of HFRT-fed mice when compared with HFAT-fed mice, which is consistent with the recent finding that palmitate and SREBP1c are implicated in hepatic oxidative stress and inflammation. These effects were associated with increased hepatic inflammation, as confirmed by high expression of markers of leukocyte infiltration in the HFRT group. Thus, we hypothesize an amplifying loop among lipogenesis, palmitate, Nrf2 and Nlrp3 that leads to a higher risk of NAFLD progression to NASH in a high-fructose diet compared to a high-saturated fat intake.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Menotti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Alessia S
authors.initials: AS
authors.lastname: Cento
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Serpe
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Dal Bello
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Romaniello
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Medana
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address: raffaella.mastrocola@unito.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects*; D058847:Inflammasomes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D036401:Toxicity Tests, Chronic
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D058847:Inflammasomes; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051779:Sterol Regulatory Element Binding Proteins; D005632:Fructose
keywords: Fructose; NAFLD; Nlrp3 inflammasome; Nrf2; SREBP1c; Saturated fat