Myeloid-specific estrogen receptor α deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development

Abstract

ERα is expressed in macrophages and other immune cells known to exert dramatic effects on glucose homeostasis. We investigated the impact of ERα expression on macrophage function to determine whether hematopoietic or myeloid-specific ERα deletion manifests obesity-induced insulin resistance in mice. Indeed, altered plasma adipokine and cytokine levels, glucose intolerance, insulin resistance, and increased adipose tissue mass were observed in animals harboring a hematopoietic or myeloid-specific deletion of ERα. A similar obese phenotype and increased atherosclerotic lesion area was displayed in LDL receptor-KO mice transplanted with ERα −/− bone marrow. In isolated macrophages, ERα was necessary for repression of inflammation, maintenance of oxidative metabolism, IL-4–mediated induction of alternative activation, full phagocytic capacity in response to LPS, and oxidized LDL-induced expression of ApoE and Abca1. Furthermore, we identified ERα as a direct regulator of macrophage transglutaminase 2 expression, a multifunctional atheroprotective enzyme. Our findings suggest that diminished ERα expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice.

Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity

“…3H) (D'Eon et al 2005), while teneligliptin suppressed the expression of Lpl, but did not affect that of Pparg or Fas in OVX-HF. On the other hand, a previous study with myeloid-specific ERa knockout mice demonstrated that estrogen attenuated chronic inflammation by directly inhibiting inflammatory responses by macrophages (Ribas et al 2011). In the present study, teneligliptin effectively attenuated chronic inflammation in the adipose tissue.…”

“…It also reportedly enhances cholesterol uptake and suppresses gluconeogenesis in the liver (Bryzgalova et al 2006). Furthermore, estrogen was shown to attenuate obesity-induced chronic inflammation in adipose tissue by repressing the inflammatory responses of macrophages (Ribas et al 2011). Previous studies reported that estrogen acted on the CNS, especially on the hypothalamus, suppressing food consumption and increasing energy expenditure, thereby protecting against body weight gain (Xu et al 2011, Yonezawa et al 2013.…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…In addition, transplant arteriosclerosis in rats or rabbits as well as macrophage infiltration into the allograft intima were potently reduced in E 2 -treated recipients, and this was associated with almost complete suppression of MHC-II antigen expression in transplanted arteries (Lou et al 1996, Saito et al 1998. Most recently, ERa-deficient macrophages were found refractory to IL4-induced activation of anti-inflammatory phenotype in vitro and presented with elevated expression of chemokines and markers of immune cell activity, when isolated from animals with myeloid-specific ERa deficiency (Ribas et al 2011). Importantly, Ldlr KO animals lacking ERa in myeloid cells showed twofold increase in atherosclerotic lesion area.…”

“…In addition, E 2 was reported to reduce macrophage uptake of modified LDLs such as acetylated, oxidized, or aggregated LDL, and this latter effect was found to specifically depend on the ERa-mediated suppression of the expression of scavenger receptor CD36 (Sulistiyani & St Clair 1997, McCrohon et al 1999, Allred et al 2006, Wilson et al 2008. More recently, ERa-deficient macrophages were shown to express reduced amounts of proteins involved in cholesterol efflux such as ABCA1 and APOE and to export less cholesterol when incubated with HDL, whereas E 2 associated with HDL particles was found to potentiate HDL-induced cholesterol efflux mediated by scavenger receptor class B type I (SR-BI (SCARB1)) (Badeau et al 2009, Ribas et al 2011. Several studies documented that HDL carries E 2 in the form of fatty acyl esters produced in a reaction catalyzed by lecithin-cholesterol acyltransferase (LCAT; Helisten et al 2001, Höckerstedt et al 2002.…”

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

“…Epidemiological studies suggest that estrogen protects women against CVD before menopause (2), and numerous animal studies have shown that estrogen significantly protects against the development of atherosclerosis (3)(4)(5). However, randomized controlled trials of postmenopausal estrogen therapy have demonstrated mixed CVD effects (6,7).…”