Abstract
Excessive iron accumulation in the liver, which accompanies certain genetic or metabolic diseases, impairs bile acids (BA) synthesis, but the influence of iron on the complex process of BA homeostasis is unknown. Thus, we evaluated the effect of iron overload (IO) on BA turnover in rats. Compared with control rats, IO (8 intraperitoneal doses of 100 mg/kg every other day) significantly decreased bile flow as a consequence of decreased biliary BA secretion. This decrease was associated with reduced expression of Cyp7a1, the rate limiting enzyme in the conversion of cholesterol to BA, and decreased expression of Bsep, the transporter responsible for BA efflux into bile. However, IO did not change net BA content in faeces in response to increased intestinal conversion of BA into hyodeoxycholic acid. In addition, IO increased plasma cholesterol concentrations, which corresponded with reduced Cyp7a1 expression and increased expression of Hmgcr, the rate-limiting enzyme in de novo cholesterol synthesis. In summary, this study describes the mechanisms impairing synthesis, biliary secretion and intestinal processing of BA during IO. Altered elimination pathways for BA and cholesterol may interfere with the pathophysiology of liver damage accompanying liver diseases with excessive iron deposition.
Highlights
Bile production is an essential function of the liver and serves as an irreplaceable excretory pathway for elimination of lipophilic endo- and xenobiotics such as cholesterol, bile acids (BA), bilirubin or drugs[1]
We showed that increased iron deposition in rat liver results in decreased bile formation due to reduced biliary BA secretion through downregulated Bsep and Mrp[2] apical transporters
iron overload (IO) with excessive liver accumulation was further confirmed by increased plasma concentrations of iron and ferritin (Fig. 1C) and by increased liver mRNA expression of key iron metabolism associated genes such as hepcidin (Hamp), ferritin (Ftl), ferroportin (Slc40a1) and down regulation of transferrin receptor 1 (Trfc) (Fig. 1B)
Summary
Bile production is an essential function of the liver and serves as an irreplaceable excretory pathway for elimination of lipophilic endo- and xenobiotics such as cholesterol, BA, bilirubin or drugs[1]. BA as the major metabolites of cholesterol, act as hormones by agonism at several receptors such as farnesoid X receptor (FXR), the G protein-coupled bile acid receptor 1 (TGR5), sphingosine-1-phosphate receptor 2, or pregnane X receptor (PXR), and regulate numerous liver functions including glucose and triglyceride metabolism[2]. Stimulation of these receptors demonstrates promising positive effects in liver diseases such as nonalcoholic steatohepatitis (NASH) or intrahepatic cholestasis[3]. Plasma concentrations of BA were not significantly affected by IO because reduced biliary BA secretion was accompanied by reduced liver BA synthesis, intestinal BA processing, and increased basolateral output from hepatocytes and reduced uptake to hepatocytes
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