title: Berry intake changes hepatic gene expression and DNA methylation patterns associated with high-fat diet.
abstract: The liver is a critical organ for regulation of energy homeostasis and fatty liver disease is closely associated with obesity and insulin resistance. We have previously found that lingonberries, blackcurrants and bilberries prevent, whereas açai berries exacerbate, the development of hepatic steatosis and obesity in the high-fat (HF)-fed C57BL/6J mouse model. In this follow-up study, we investigated the mechanisms behind these effects. Genome-wide hepatic gene expression profiling indicates that the protective effects of lingonberries and bilberries are accounted for by several-fold downregulation of genes involved in acute-phase and inflammatory pathways (e.g. Saa1, Cxcl1, Lcn2). In contrast, açai-fed mice exhibit marked upregulation of genes associated with steatosis (e.g. Cfd, Cidea, Crat) and lipid and cholesterol biosynthesis, which is in line with the exacerbation of HF-induced hepatic steatosis in these mice. In silico transcription factor analysis together with immunoblot analysis identified NF-κB, STAT3 and mTOR as upstream regulators involved in mediating the observed transcriptional effects. To gain further insight into mechanisms involved in the gene expression changes, the HELP-tagging assay was used to identify differentially methylated CpG sites. Compared to the HF control group, lingonberries induced genome-wide hypermethylation and specific hypermethylation of Ncor2, encoding the corepressor NCoR/SMRT implicated in the regulation of pathways of metabolic homeostasis and inflammation. We conclude that the beneficial metabolic effects of lingonberries and bilberries are associated with downregulation of inflammatory pathways, whereas for blackcurrants, exerting similar metabolic effects, different mechanisms of action appear to dominate. NF-κB, STAT3 and mTOR are potential targets of the health-promoting effects of berries.
authors.affiliation: Department of Experimental Medical Science, Lund University Biomedical Centre, SE-221 84 Lund, Sweden. Electronic address: lovisa.heyman@med.lu.se.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Heyman-Lindén
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 104 61, USA. Electronic address: yoshinori.seki@einstein.yu.edu.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Department of Clinical Sciences, Lund University Clinical Research Centre, SE-205 02 Malmö, Sweden. Electronic address: petter.storm@med.lu.se.
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Department of Experimental Medical Science, Lund University Biomedical Centre, SE-221 84 Lund, Sweden. Electronic address: helena.jones@med.lu.se.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Jones
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 104 61, USA; Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 104 61, USA; Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 104 61, USA. Electronic address: maureen.charron@einstein.yu.edu.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.affiliation: Department of Experimental Medical Science, Lund University Biomedical Centre, SE-221 84 Lund, Sweden. Electronic address: karin.berger@med.lu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Berger
authors.affiliation: Department of Experimental Medical Science, Lund University Biomedical Centre, SE-221 84 Lund, Sweden. Electronic address: cecilia.holm@med.lu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Holm
mesh_terms: D000818:Animals; D019175:DNA Methylation; D004032:Diet; D059305:Diet, High-Fat; D005638:Fruit; D015870:Gene Expression; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: Berries; Gene expression; High-fat diet; Inflammation; Liver steatosis; Methylation