Hepatic overexpression of Abcb 11 in mice promotes the conservation of bile acids within the 1 enterohepatic circulation

29 INTRODUCTION: The Bile Salt Export Pump, encoded by ABCB11, is the predominant canalicular 30 transport protein for biliary bile acid secretion. The level of ABCB11 expression in humans is widely 31 variable yet the impact of this variability on human disease is not well-defined. We aim to determine 32 the effect of hepatic Abcb11 overexpression on the enterohepatic circulation (EHC) in mice. 33 METHODS: We used a stable isotope dilution technique in transgenic mice overexpressing hepatic 34 Abcb11 (TTR-Abcb11) to determine the pool size, fractional turnover rate (FTR), and synthesis rate of 35 the primary bile acid, cholic acid (CA). The gallbladder was cannulated to determine bile flow, bile 36 acid composition, and the biliary secretion rates of CA, total bile acids, phospholipid and cholesterol. 37 The combined data allowed for estimation of the CA cycling time and the fraction of CA lost per 38 cycle. Hepatic and intestinal gene and protein expression were determined by qPCR and Western blot. 39 RESULTS: Abcb11 overexpression strongly decreased FTR and synthesis rate of CA. Abcb11 40 overexpression decreased the fraction of CA that was lost per cycle of the EHC. Hepatic expression of 41 Cyp7a1 was suppressed by nearly 50% and ileal expression of FGF15 was increased >8-fold in TTR42 Abcb11 mice. Despite the increased intestinal reabsorption of bile acids, ileal Asbt expression was 43 suppressed. CONCLUSIONS: Hepatic Abcb11 overexpression in mice increases the conservation of 44 bile acids within the enterohepatic circulation. These data provide strong evidence for the existence of 45 feed-forward communication between hepatic expression of a bile acid transport protein and the 46 intestine. 47 48