title: Involvement of interleukin-1 in lead nitrate-induced hypercholesterolemia in mice.
abstract: Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and cholesterol 7α-hydroxylase (Cyp7a1) are rate-limiting enzymes for cholesterol biosynthesis and catabolism, respectively. Involvement of inflammatory cytokines, particularly interleukin-1 (IL-1), in alterations of HMGR and Cyp7a1 gene expression during development of lead nitrate (LN)-induced hypercholesterolemia was examined in IL-1α/β-knockout (IL-1-KO) and wild-type (WT) mice. Lead nitrate treatment of WT mice led to not only a marked downregulation of the Cyp7a1 gene at 6-12 h, but also a significant upregulation of the HMGR gene at 12 h. However, such changes were not observed at significant levels in IL-1-KO mice, although a slight, transient downregulation of the Cyp7a1 gene and a minimal upregulation of the HMGR gene occurred at 6 h and 24 h, respectively. Consequently, LN treatment led to development of hypercholesterolemia at 24 h in WT mice, but not in IL-1-KO mice. Furthermore, in WT mice, significant LN-mediated increases were observed at 3-6 h in hepatic IL-1 levels, which can modulate gene expression of Cyp7a1 and HMGR. These findings indicate that, in mice, LN-mediated increases in hepatic IL-1 levels contribute, at least in part, to altered expressions of Cyp7a1 and HMGR genes, and eventually to hypercholesterolemia development.
authors.affiliation: Animal Genome Research Unit, Agrogenomics Research Center, National Institute of Agrobiological Sciences, Tsukuba, Japan. misaki@affrc.go.jp
authors.forename: Misaki
authors.initials: M
authors.lastname: Kojima
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashino
authors.forename: Takemi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Masakuni
authors.initials: M
authors.lastname: Degawa
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006937:Hypercholesterolemia / Q000139:chemically induced* / Q000378:metabolism; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009566:Nitrates / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D058886:Sterol 14-Demethylase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D004785:Environmental Pollutants; D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D009566:Nitrates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007854:Lead; C017461:lead nitrate; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse