The bile salt export pump (BSEP or ABCB11) mediates the adenosine triphosphate-dependent transport of bile salts across the canalicular membrane of the hepatocyte. Mutations in the corresponding ABCB11 gene cause progressive familial intrahepatic cholestasis type 2. The aim of this study was to investigate the regulation of human ABCB11 gene transcription by bile salts. First, a 1.7-kilobase human ABCB11 promoter region was cloned. Sequence analysis for possible regulatory elements showed a farnesoid X receptor responsive element (FXRE) at position ؊180. Progressive familial intrahepatic cholestasis comprises a number of inherited liver diseases of childhood that are characterized by cholestasis and jaundice leading to cirrhosis. 3 In patients with progressive familial intrahepatic cholestasis type 2, cholestasis is a result of impaired secretion of bile salts into canaliculi caused by mutations in the ABCB11 gene. 4 The ABCB11 protein (previously named sister of P-glycoprotein or bile salt export pump) is a member of the P-glycoprotein subfamily and is the major canalicular bile salt transporter. 5 To maintain bile salt homeostasis, both bile salt synthesis and hepatobiliary transport are strictly controlled processes. For instance, at increased bile salt concentrations in the blood, hepatic uptake and bile salt biosynthesis are down-regulated, whereas canalicular transport into bile is up-regulated. 6 Recently, a number of bile salts have been shown to bind and strongly activate the nuclear hormone receptor farnesoid X receptor (FXR) at physiologic concentrations. 7-9 FXR is active in a heterodimer with the 9-cis retinoic acid receptor retinoid X receptor ␣ (RXR␣) and binds to an inverted repeat element with a 1-base pair spacing (IR-1) between the two 6 -base pair half-sites. 10

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Background & Aims Systemic retinol (vitamin A) homeostasis is controlled by the liver, involving close collaboration between hepatocytes and hepatic stellate cells (HSCs). Genetic variants in retinol metabolism ( PNPLA3 and HSD17B13 ) are associated with non-alcoholic fatty liver disease (NAFLD) and disease progression. Still, little mechanistic details are known about hepatic vitamin A metabolism in NAFLD, which may affect carbohydrate and lipid metabolism, inflammation, oxidative stress and the development of fibrosis and cancer, e.g. all risk factors of NAFLD. Methods Here, we analyzed vitamin A metabolism in 2 mouse models of NAFLD; mice fed a high-fat, high-cholesterol (HFC) diet and Leptin ob mutant ( ob/ob ) mice. Results Hepatic retinol and retinol binding protein 4 (RBP4) levels were significantly reduced in both mouse models of NAFLD. In contrast, hepatic retinyl palmitate levels (the vitamin A storage form) were significantly elevated in these mice. Transcriptome analysis revealed a hyperdynamic state of hepatic vitamin A metabolism, with enhanced retinol storage and metabolism (upregulated Lrat, Dgat1, Pnpla3 , Raldh’s and RAR/RXR-target genes) in fatty livers, in conjunction with induced hepatic inflammation (upregulated Cd68 , Tnfα , Nos2 , Il1β, Il-6 ) and fibrosis (upregulated Col1a1 , Acta2 , Tgfβ , Timp1 ). Autofluorescence analyses revealed prominent vitamin A accumulation in hepatocytes rather than HSC in HFC-fed mice. Palmitic acid exposure increased Lrat mRNA levels in primary rat hepatocytes and promoted retinyl palmitate accumulation when co-treated with retinol, which was not detected for similarly-treated primary rat HSCs. Conclusion NAFLD leads to cell type-specific rearrangements in retinol metabolism leading to vitamin A accumulation in hepatocytes. This may promote disease progression and/or affect therapeutic approaches targeting nuclear receptors.