Hepatic arginine and lysine uptake is partly regulated by changes in the transport activity of a group of cell surface proteins exhibiting properties of the transport system y+. The Cat-1 gene encodes a sodium-independent high-affinity cationic amino acid transporter of the y+ system which is nearly undetectable in the quiescent liver. In this paper we investigate the regulation of expression of Cat-1 in the quiescent rat liver by glucocorticoids and insulin, two hormones which play a critical role in amino acid dependent pathways of hepatic metabolism. Injection of insulin and glucocorticoids resulted in a rapid (15-30 min, 4-5 fold) increase in transcription which returned to basal levels within 4 hours. In contrast to the rapid single peak of transcriptional induction of the Cat-1 gene, the accumulation of the Cat-1 mRNAs occurred transiently with two peaks, the first at 30 minutes and the second at 2-4 hours following hormone treatment. These data indicate that expression of the Cat-1 gene in the quiescent liver can be transiently induced by both transcriptional and post-transcriptional mechanisms. In FTO2B rat hepatoma cells, expression of the gene is constitutive and accumulation of Cat-1 mRNAs in response to dexamethasone and insulin was dependent on transcription and protein synthesis. Furthermore, the accumulation of the basal level of the Cat-1 mRNAs was reduced by 70%, upon treatment of cells with inhibitors of protein synthesis for 6 h, when the transcription rate of the gene did not decrease significantly. We conclude the following: (i) under normal physiologic conditions, expression of the Cat-1 gene in the quiescent liver is negligible, probably to prevent unnecessary transport and metabolism of arginine by the hepatic arginase in the hepatocytes. (ii) in the cases when hepatic cationic amino acid transport is needed, such as following feeding, cellular growth and illness, glucocorticoids and insulin induce expression of the Cat-1 gene in liver cells through induction of transcription and stabilization of the mRNA. (iii) constitutive Cat-1 mRNA accumulation in rat hepatoma cells depends on protein synthesis through a labile regulated factor. Overall, constitutive expression of Cat-1 is associated with hepatic cellular growth and transformation.

and transvaginal ultrasound), and changes in bone mineral density (BMD) were assessed. RESULTS: In Cohort 1, 259 women were randomized and treated; 80% completed treatment. Cohort 1 responses for the primary endpoint were 92% elagolix alone, 85% elagolix+LDA, 79% elagolix+SDA, and 27% placebo (all p< .001 vs. placebo). Elagolix treatment alone was associated with hot flushes and a decrease in BMD; add-back therapy attenuated these hypoestrogenic effects in a dose-dependent manner. At month 6, the most common endometrial biopsy category from women in elagolix groups was normal quiescent/minimally stimulated endometrium. All groups had a decrease in endometrial thickness (mean change from baseline to month 6 in mm: elagolix alone ¼ -0.52, elagolix+LDA ¼ -1.33 [p%.05 vs. placebo], elagolix+SDA ¼ -0.56, placebo ¼ 2.1). Similar efficacy and safety results were observed in Cohort 2. CONCLUSIONS: Elagolix with or without add-back significantly reduced MBL in UF-associated HMB. Add-back therapy attenuated the hypoestrogenic effects of elagolix. There were no adverse endometrial findings.

achieving amenorrhea and time to amenorrhea. Both UPA 10 mg and 5 mg were generally well tolerated. Numerically greater responses in efficacy were observed with UPA 10 mg vs 5 mg, though the safety profiles were similar.

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