title: Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet.
abstract: Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.
authors: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yoshihiro
authors: Y
authors: Kamada
authors: Shinichi
authors: S
authors: Kiso
authors: Yuichi
authors: Y
authors: Yoshida
authors: Norihiro
authors: N
authors: Chatani
authors: Takashi
authors: T
authors: Kizu
authors: Mina
authors: M
authors: Hamano
authors: Mayumi
authors: M
authors: Tsubakio
authors: Takayo
authors: T
authors: Takemura
authors: Hisao
authors: H
authors: Ezaki
authors: Norio
authors: N
authors: Hayashi
authors: Tetsuo
authors: T
authors: Takehara
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D059305:Diet, High-Fat; D004967:Estrogens / Q000172:deficiency* / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000502:physiology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D065626:Non-alcoholic Fatty Liver Disease; D010052:Ovariectomy; D017698:Postmenopause / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000235:genetics; D012307:Risk Factors
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D004967:Estrogens; D008074:Lipoproteins; D054390:Receptors, CCR2; C030104:lipoprotein cholesterol; D002784:Cholesterol