Nonnuclear estrogen receptor activation improves hepatic steatosis in female mice

Ken L. Chambliss, Jose Barrera, Michihisa Umetani, Junko Umetani, Sung Hoon Kim, Zeynep Madak-Erdogan, Linzhang Huang, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Chieko Mineo, Philip W. Shaul

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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 cancerpromoting 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, E2 and 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 E2 caused 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.

Original languageEnglish (US)
Pages (from-to)3731-3741
Number of pages11
Issue number10
StatePublished - 2016

ASJC Scopus subject areas

  • Endocrinology


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