The Influence of Estrogen on Hepatobiliary Osteopontin (SPP1) Expression in a Female Rodent Model of Alcoholic Steatohepatitis

Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA.
Toxicologic Pathology (Impact Factor: 2.14). 05/2009; 37(4):492-501. DOI: 10.1177/0192623309335633
Source: PubMed


Our recent studies suggest that higher neutrophil infiltration in females correlates with increased hepatobiliary expression of osteopontin (OPN) in alcoholic steatohepatitis (ASH). The objective of this study was to understand the role of alcohol in altering estrogen levels in females by examining the effect of ethanol (EtOH) on the estrous cycle and then investigate the potential relationship between estradiol (E2) and hepatobiliary OPN expression in a female rat ASH model. Ovariectomized (OVX) and E2-implanted OVX rats in the ASH group were evaluated for OPN mRNA and protein expression. Low doses of E2 resulted in significant down-regulation of OPN protein and mRNA as compared to the OVX group. However, with increasing doses of E2, there was up-regulation of both OPN mRNA and protein. Osteopontin was localized primarily to the biliary epithelium. Liver injury assessed by serum ALT and histopathology revealed a pattern similar to OPN expression. In all groups, hepatic neutrophilic infiltration correlated positively with OPN expression. Based on these data, we conclude that in our ASH model, low doses of E2 appear to be hepatoprotective, whereas the protective effect appears to diminish with increasing doses of E2, although additional cause and effect studies are needed for confirmation.

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Available from: Robert C Burghardt, Dec 23, 2014
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    • "Furthermore, the hepatic feminization in males through an increase in estrogen receptors may protect liver from severe alcohol-induced injury [25]. Whereas low doses of estradiol appear to be hepatoprotective, this effect diminishes with increasing doses [26]. "
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    • "It has been reported that polyunsaturated fatty acids play an important role in the pathogenesis of alcoholic liver disease (Polavarapu et al., 1998; Nanji, 2004; Purohit et al., 2004). Female rats in the alcohol-induced liver injury model experience signifi-cantly more severe liver injury than the males (Polavarapu et al., 1998; Banerjee et al., 2009; Eagon, 2010). In view of the above, hepatic steatosis was induced by ethanol gavage plus diet such as corn oil which is rich in unsaturated fatty acids for 6 weeks in our study. "
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    • "In addition, circulating osteopontin was also correlated with female sex hormones. Of note, estrogen was reported to increase hepato-biliary osteopontin expression [27]. Moreover, interactions between estrogen and osteopontin have been described in other tissues as well [28]. "
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    ABSTRACT: Reciprocal interaction between bone and glucose metabolism might play a pivotal role in the development of type 2 diabetes. We recently demonstrated that osteocalcin is increased in women with gestational diabetes (GDM) compared to healthy pregnant women and related to enhanced insulin secretion. Here, we aimed to investigate the role of the bone resorption marker CTX and osteopontin (OPN), a key molecule in subclinical inflammation underlying insulin resistance, in gestational diabetes. Insulin sensitivity and secretion (derived from OGTT) as well as CTX and osteopontin were investigated in 26 GDM and 52 women with normal glucose tolerance during pregnancy [CON] between 24th and 28th gestational weeks; 24 women also underwent postpartum examination. CTX was significantly higher in GDM compared to CON (0.44±0.20 vs.0.28±0.12 ng/ml, p<.0001) and positively correlated with osteocalcin (R = 0.64, p<.0001) and parameters of insulin secretion. Osteopontin plasma concentrations were decreased in GDM compared to CON (28.81±22.12 vs.37.68±19.63 ng/ml, p = 0.04), and did not show any relation to insulin secretion or sensitivity, but were significantly correlated with CRP (R = 0.3, p<0.007) and liver enzymes. Twelve weeks after delivery CTX and OPN were increased compared to pregnancy (both p<.0001) and did not differ between GDM and CON. Our findings support the idea of a tight regulation between bone and glucose metabolism, and suggest, that less curbed CTX during pregnancy might be involved in osteocalcin-mediated amelioration of insulin secretion in GDM. On the other hand, osteopontin was unrelated to insulin resistance in GDM, but associated with inflammatory markers and liver enzymes in all women.
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