Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models.
Four new mimics of 22-S-hydroxycholesterol (22SHC) were synthesized and evaluated using molecular modeling and tested in human muscle cells (primary myotubes) and hepatocytes (HepG2 cells). The new compounds (9, 12, 15a and 15b) showed good interrelationship between docking scores, to both LXRα and LXRβ, and in vitro results. The LXR agonist T0901317 increased the expressions of genes involved in lipogenesis (SCD1, FAS) and cholesterol efflux (ABCA1), but only 22SHC counteracted the up-regulation of SCD1 and FAS by T0901317. Compound 9 and 12 decreased the expression of SCD1, while 9 also decreased the expression of FAS. Compounds 15a showed a significant antagonistic effect on ABCA1 expression, but neither 15a nor 15b were able to counteract the effect of T0901317 on all genes examined. Lipogenesis was increased after T0901317 treatment and only 22SHC significantly counteracted this effect. Treatment with 22SHC and compound 12 reduced lipogenesis compared to control. An increased glucose uptake was observed for all compounds, except for 15b. In summary, the new synthetic 22SHC mimics showed antagonistic effects similar to that of 22SHC, but the new substances were less potent. The sulfonamide 12 showed similar effects to 22SHC and the best effect on gene expression of the new mimics, however, it was not able to reduce the effect of T0901317 as observed for 22SHC.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Oslo, Norway.
Ove Alexander
OA
Høgmoen Åstrand
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway.
Ingvei
I
Gikling
Medicinal Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, The Artic University of Norway, Tromsø, Norway.
Ingebrigt
I
Sylte
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway.
Arild Christian
AC
Rustan
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
G Hege
GH
Thoresen
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Oslo, Norway.
Pål
P
Rongved
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316 Oslo, Norway. Electronic address: e.t.kase@farmasi.uio.no.
Eili Tranheim
ET
Kase
D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D000071518:Liver X Receptors; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000187:drug effects*
D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors
Gene regulation; LXR modulators; Lipid metabolism; Molecular modeling; Type 2 diabetes