title: Nonnuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice.
abstract: Estrogens have the potential to afford atheroprotection, to prevent excess adiposity and its metabolic complications including insulin resistance, and to lessen hepatic steatosis. Cellular responses to estrogens occur through gene regulation by nuclear estrogen receptors (ERs), and through signal initiation by plasma membrane-associated ER. Leveraging the potentially favorable cardiometabolic actions of estrogens has been challenging, because their reproductive tract and cancer-promoting effects adversely impact the risk to benefit ratio of the therapy. In previous works, we discovered that an estrogen dendrimer conjugate (EDC) comprised of ethinyl-estradiol (E2) molecules linked to a poly(amido)amine dendrimer selectively activates nonnuclear ER, and in mice, EDC does not invoke a uterotrophic response or support ER-positive breast cancer growth. In the present investigation, we employed EDC to determine how selective nonnuclear ER activation impacts atherosclerosis, adiposity, glucose homeostasis, and hepatic steatosis in female mice. In contrast to E2, EDC did not blunt atherosclerosis in hypercholesterolemic apoE-/-mice. Also in contrast to E2, EDC did not prevent the increase in adiposity caused by Western diet feeding in wild-type mice, and it did not affect Western diet-induced glucose intolerance. However, E2and EDC had comparable favorable effect on diet-induced hepatic steatosis, and this was related to down-regulation of fatty acid and triglyceride synthesis genes in the liver. Predictably, only E2caused a uterotrophic response. Thus, although nonnuclear ER activation does not prevent atherosclerosis or diet-induced obesity or glucose intolerance, it may provide a potential new strategy to combat hepatic steatosis without impacting the female reproductive tract or increasing cancer risk.
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Jose
authors.initials: J
authors.lastname: Barrera
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Junko
authors.initials: J
authors.lastname: Umetani
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Linzhang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Center for Pulmonary and Vascular Biology (K.L.C., J.B., M.U., J.U., L.H., C.M., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, 75390; and Departments of Chemistry (S.H.K., J.A.K.), Food Science and Human Nutrition (Z.M.-E.), and Molecular and Integrative Physiology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects; D050091:Dendrimers / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008810:Mice, Inbred C57BL
chemical_list: D050091:Dendrimers; D004967:Estrogens; D005947:Glucose