Regulation of SNAT4 by HNF4α was examined by promoter analyses and electrophoretic mobility shift assays (EMSA). Metabolic labeling and western blotting were carried out using primary hepatoblasts with SNAT4 overexpression. The expression of Slc38a4 encoding SNAT4 showed a marked perinatal increase, and was predominant among system A amino acid transporters. It was first detected

in embryonic day 18.5 liver, and found in most hepatocytes after birth. Three alternative first exons were found in the SNAT4 gene. Promoter analyses using approximately 3-kb fragments corresponding to each first exon (AP1, AP2, AP3) revealed that AP1 and AP2 exhibited strong promoter activity in mouse hepatoblasts with endogenous HNF4α. Transactivation of AP2 was upregulated by HNF4α

in HeLa cells without endogenous HNF4α. EMSA has demonstrated that HNF4α directly binds check details to cis-elements in AP2. Overexpression of SNAT4 facilitated amino acid uptake and de novo protein synthesis in primary hepatoblasts. SNAT4 functions downstream of HNF4α and plays significant roles in liver development through mechanisms of amino acid uptake and protein synthesis. “
“BSP bromsulfaphein TUNEL transferase-mediated dUTP nick end labeling Raf inhibitor In a fascinating study, Cai et al.1 examined how the sea lamprey adapts to a programmed disappearance of the gallbladder, intra- and extrahepatic bile ducts, and bile canaliculi. The investigators studied bile acid and xenobiotic homoeostasis, and used molecular biological profiling to define

the expression of transporters in the liver and kidney of lamprey larvae and adults. Adult livers were severely cholestatic as assessed by high bile salt levels but had no evidence of cytological damage such is the necrosis, fibrosis, or inflammation. In both larvae and adults plasma bile acid levels were maintained at a low level, even though the adult MCE livers lack a biliary system. One mechanism for adaptation in the adults is to transform C 24 bile acids to C 27 bile acids. The authors found that petromyzonol sulfate, the major bile salt in lamprey larvae is cytotoxic, but is converted to the less toxic 3-keto-petromyzonol sulfate in the adult. Interestingly, apical canalicular transporters could be detected by immunochemical methods only in the livers of larvae. Additional experiments showed that the main route of excretion in the adult for bromsulfaphein (BSP) and bile acids was through the urine. In keeping with this observation they found through gene expression studies that there was marked up-regulation of orthologs for organic anion and bile acid transporters in the kidneys. Atresia is commonly defined as the congenital absence or pathological closure of an opening, passage, or cavity. In all organisms, save the sea lamprey, the process is pathological in organs such as the esophagus, intestine, and biliary tract caused by a failure of normal development or by acquired destruction usually via inflammatory or vascular mechanisms.