Retinoic acid signaling positively regulates liver specification by inducing wnt2bb gene expression in medaka.

UNLABELLED: During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost. CONCLUSION: Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. These results suggest that a common molecular mechanism may underlie liver and pectoral fin specification during piscine embryogenesis.

Hypotensive and lipid regulatory actions of 4-hydroxyderricin, a chalcone from Angelica keiskei, in stroke-prone spontaneously hypertensive rats.

1. Previously, we found that Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems) elevated serum high-density lipoprotein (HDL) levels and reduced liver triglyceride content in stroke-prone spontaneously hypertensive rats (SHRSP). To identify the active substance in A. keiskei extract, we examined the effect of 4-hydroxyderricin, a characteristic chalcone isolated from the yellow liquid of stems, on blood pressure and lipid metabolism in SHRSP. 2. Six-week-old male SHRSP were fed diets containing 0.07% 4-hydroxyderricin for 7 weeks with free access to the diet and water. Elevation of systolic blood pressure was significantly suppressed after 7 weeks treatment. Serum very low-density lipoprotein (VLDL) levels were significantly reduced, without any effect on HDL levels, and were associated with a significant decrease in the serum concentration of free fatty acids. 3. In the liver, significant decreases in relative liver weight and triglyceride content were found after treatment with 4-hydroxyderricin for 7 weeks. 4. An investigation of hepatic mRNA expression of proteins involved in lipid metabolism indicated that a significant decrease in microsomal triglyceride transferprotein may be responsible for the decrease in serum VLDL levels and that significant decreases in adipocyte determination and differentiation factor 1 and fatty acid synthase may be responsible for the decrease in hepatic triglyceride content. 5. In conclusion, dietary 4-hydroxyderricin produces suppression of the elevation of systolic blood pressure, reduction of serum VLDL levels and a decrease in hepatic triglyceride content in SHRSP.