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Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK rat model of ARPKD. T1 relaxation time results were obtained for five PCK rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK rats exhibited significantly increased liver T1 values (mean ± standard deviation = 935 ± 39 ms) compared with age-matched SD control rats (847 ± 26 ms, p = 0.01). One PCK rat exhibited severe cholangitis (mean T1 = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent ( R = 0.85, p = 0.002), periportal fibrosis area percent ( R = 0.82, p = 0.004), and hydroxyproline content ( R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non-invasive imaging biomarker to monitor ARPKD liver disease. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, holo-RBP is recognized by a plasma membrane receptor termed STRA6, which serves a dual role: it mediates transport of retinol from RBP into cells, and it functions as a cytokine receptor that, on binding holo-RBP, activates JAK2/STAT5 signaling. As STAT target genes include SOCS3, an inhibitor of insulin receptor, holo-RBP suppresses insulin responses in STRA6-expressing cells. We have shown previously that the two functions of STRA6 are interdependent. These observations suggest factors that regulate STRA6-mediated retinol transport may also control STRA6-mediated cell signaling. One such factor is retinol metabolism, which enables cellular uptake of retinol by maintaining an inward-directed concentration gradient. We show here that lecithin:retinol acyl transferase (LRAT), which catalyzes esterification of retinol to its storage species retinyl esters, is necessary for activation of the STRA6/JAK2/STAT5 cascade by holo-RBP. In accordance, LRAT-null mice are protected from holoRBP-induced suppression of insulin responses. Hence, STRA6 signaling, which requires STRA6-mediated retinol transport, is supported by LRAT-catalyzed retinol metabolism. The observations demonstrate that STRA6 regulates key cellular processes by coupling circulating holo-RBP levels and intracellular retinol metabolism to cell signaling. [ABSTRACT FROM AUTHOR]

Background Because the histological and biochemical progression of liver disease is similar in alcoholic steatohepatitis ( ASH) and nonalcoholic steatohepatitis ( NASH), we hypothesized that the genetic susceptibility to these liver diseases would be similar. To identify potential candidate genes that regulate the development of liver fibrosis, we studied a chromosome substitution strain ( CSS-17) that contains chromosome 17 from the A/ J inbred strain substituted for the corresponding chromosome on the C57 BL/6 J (B6) genetic background. Previously, we identified quantitative trait loci ( QTLs) in CSS-17, namely obesity-resistant QTL 13 and QTL 15 ( Obrq13 and Obrq15, respectively), that were associated with protection from diet-induced obesity and hepatic steatosis on a high-fat diet. Methods To test whether these or other CSS-17 QTLs conferred resistance to alcohol-induced liver injury and fibrosis, B6, A/ J, CSS-17, and congenics 17 C-1 and 17 C-6 were either fed Lieber- De Carli ethanol ( Et OH)-containing diet or had carbon tetrachloride ( CCl4) administered chronically. Results The congenic strain carrying Obrq15 showed resistance from alcohol-induced liver injury and liver fibrosis, whereas Obrq13 conferred susceptibility to liver fibrosis. From published deep sequencing data for chromosome 17 in the B6 and A/ J strains, we identified candidate genes in Obrq13 and Obrq15 that contained single-nucleotide polymorphisms ( SNPs) in the promoter region or within the gene itself. NADPH oxidase organizer 1 ( Noxo1) and NLR family, CARD domain containing 4 ( Nlrc4) showed altered hepatic gene expression in strains with the A/ J allele at the end of the Et OH diet study and after CCl4 treatment. Conclusions Aspects of the genetics for the progression of ASH are unique compared to NASH, suggesting that the molecular mechanisms for the progression of disease are at least partially distinct. Using these CSSs, we identified 2 candidate genes, Noxo1 and Nlrc4, which modulate genetic susceptibility in ASH. [ABSTRACT FROM AUTHOR]

The cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) has been proven to play an important role in both carbohydrate and lipid metabolism. PEPCK-C gene is expressed primarily in the liver, kidney, adipose tissue, and the mammary gland. Because the role of PEPCK-C in mammary gland is still unclear, we proposed to test the role of PEPCK-C gene in the mammary gland. The mammary gland is composed of two cell types, adipocytes and epithelial cells. We hypothesize that PEPCK-C is required for glyceroneogenesis. By the deletion analysis of PEPCK-C promoter, we found the region from -- 490bp to -260bp is required for the expression of PEPCK-C gene in NMuMG cells, a mammary epithelial cell line. We are investigating the regulation of PEPCK-C in the NMuMG cells. [ABSTRACT FROM AUTHOR]