The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp.

BACKGROUND AND AIMS: Hepatic bile acid homeostasis is regulated by negative feedback inhibition of genes involved in the uptake and synthesis of bile acids. Bile acids down-regulate the rate-limiting gene for bile acid synthesis, cholesterol 7alpha-hydroxylase (cyp7a), via bile acid receptor (fxr) activation of an inhibitory nuclear receptor, shp. We hypothesized that shp would also mediate negative feedback regulation of ntcp, the principal hepatic bile acid transporter. METHODS: Primary rat hepatocytes or transfected HepG2 and Cos cells were treated with retinoids with or without bile acids, and effects on bile acid transport and ntcp and shp gene expression and promoter activity were determined. Gel shift assays were performed using synthetic fxr, rxr, and rar proteins. RESULTS: Bile acid treatment of primary rat hepatocytes prevented retinoid activation of ntcp gene expression and function; this corresponded temporally with shp gene activation. Bile acid-mediated down-regulation occurred via fxr-dependent suppression of the ntcp RXR:RAR response element. Moreover, cotransfected shp directly inhibited retinoid activation of the ntcp promoter. CONCLUSIONS: These studies show negative feedback regulation of ntcp by bile acid-activated fxr via induction of shp. This novel regulatory pathway provides a means for coordinated down-regulation of bile acid import and synthesis, thereby protecting the hepatocyte from bile acid-mediated damage in cholestatic conditions.

Managing a sound portable gauge radiation safety program.

At some construction engineering companies, individuals with no background in radiation safety sometimes are assigned the not always welcome title of Radiation Safety Officer (RSO). With this new title comes the responsibility of ensuring that portable gauges are used safely at their facilities and in tile field. These newly appointed RSOs sometimes lack the knowledge and experience needed to manage a radiation safety program. This article was developed to provide the basic information needed to work confidently and safely around these instruments and to discuss licensing requirements and other information pertaining to the management of a portable gauge radiation safety program.

Endotoxin-stimulated macrophages decrease bile acid uptake in WIF-B cells, a rat hepatoma hybrid cell line.

Endotoxemia leads to cytokine-mediated alterations of the hepatocellular sodium-taurocholate-cotransporting polypeptide (ntcp). We hypothesized that stimulated macrophages are essential transducers for down-regulating hepatocellular bile salt uptake in response to endotoxin (lipopolysaccharide [LPS]) exposure. Using an in vitro model, we exposed mouse macrophages (IC-21 cell line) to LPS for 24 hours. Concentrations of cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 increased 10.6-fold, 12.5-fold, and 444-fold, respectively, in LPS-conditioned IC-21 medium (CM) versus unconditioned IC-21 medium (UM). WIF-B rat hepatoma hybrid cells were incubated with either CM or UM or treated directly with medium containing recombinant TNF-alpha, IL-1beta, and IL-6. [(3)H]Taurocholate ([(3)H]TC) uptake decreased in WIF-B cells exposed to either TNF-alpha (54% of control), IL-1beta (78%), IL-6 (55%) as single additives, or in triple combination (TCC) (43%). A virtually identical decrease was observed after exposing WIF-B cells to CM (52%, P <.001). LPS had no direct effect on [(3)H]TC uptake. CM treatment did not decrease L-alanine transport in WIF-B cells. Blocking antibodies against TNF-alpha, IL-1beta, and IL-6 restored the diminished [(3)H]TC uptake in cells exposed to TCC and CM to 87% and 107% of controls, respectively. Northern blotting revealed that ntcp messenger RNA (mRNA) expression was significantly reduced in WIF-B cells after exposure to CM, and in primary rat hepatocytes exposed to CM or TNF-alpha (68%, 14%, and 29% of control, respectively). We conclude that macrophages and their ability to secrete the cytokines TNF-alpha, IL-1beta, and IL-6 may be essential in mediating the endotoxin-induced cholestatic effect of decreased hepatocellular bile salt uptake.

Basic radiation protection considerations in dental practice.

This article provides basic guidance to radiation safety professionals unfamiliar with dental radiography on how to optimize the use of x-ray equipment and maintain occupational and non-occupational doses ALARA. Topics discussed in this article include basic protective measures commonly used to minimize the patient and operator's exposure to radiation, recommendations for the development of operating procedures, and the performance of compliance audits in dental practice.

Reproductive Ecology of an Intertidal Brachyuran Crab, Sesarma sp. (nr. reticulatum), from the Gulf of Mexico.

The natural history and reproductive ecology of a presently undescribed marsh crab endemic to the Gulf of Mexico were studied in both the laboratory and the field. Weekly sampling of populations in coastal Louisiana allowed us to determine the periodicity of molting and ovarian development, as well as the seasonal variation in egg laying and size of individual egg masses. Timing of molt, egg laying, and egg hatching were monitored in individual females under simulated tidal cycles in laboratory mesocosms. Peak periods of reproductive activity in Louisiana coincide with favorable temperatures and elevated primary productivity in coastal waters. Size cohort and fecundity differ between these periods. Egg-laying, larval release, and molting observed in individual females in the laboratory and extrapolated dates of egg-laying and larval release for those in field samples exhibit a semilunar influence throughout the season. Female receptivity to mating is tied to egg-laying. Rate of embryonic development was associated with decreases and increases in egg size. Behavior related to larval release is described. Adaptive significance in relation to the intertidal marsh habitat is discussed.