Inhibition of hepatic apolipoprotein A-I gene expression by histamine.

In a recent high throughput analysis to identify drugs that alter hepatic apolipoprotein A-I (apo A-I) expression, histamine receptor one (H1) antagonists emerged as potential apo A-1 inducing drugs. Thus the present study was undertaken to identify some of the underlying molecular mechanisms of the effect of antihistaminic drugs on apo AI production. Apo A-I levels were measured by enzyme immunoassay and Western blots. Apo A-I mRNA levels were measured by reverse transcription real-time PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as the internal control. The effects of histamine and antihistamines on apo A-I gene were determined by transient transfection of plasmids containing the apo A-I gene promoter. Histamine repressed while (H1) receptor antagonist azelastine increased apo A-I protein and mRNA levels within 48 h in a dose-dependent manner. Azelastine and histamine increased and suppressed, respectively, apo A-I gene promoter activity through a peroxisome proliferator activated receptor α response element. Treatment of HepG2 cells with other H1 receptor antagonists including fexofenadine, cetirizine, and diphenhydramine increased apo A-I levels in a dose-dependent manner while treatment with H2 receptor antagonists including cimetidine, famotidine, and ranitidine had no effect. We conclude that H1 receptor signaling is a novel pathway of apo A1 gene expression and therefore could be an important therapeutic target for enhancing de-novo apo A-1 synthesis.

High-Throughput Analysis Identifying Drugs That Regulate Apolipoprotein A-I Synthesis.

Apolipoprotein A-I (apo A-I) is the primary antiatherogenic protein in high-density lipoprotein (HDL). Despite the controversy as to the clinical effectiveness of raising HDL, the search is ongoing for safe and effective drugs that increase HDL and apo A-I levels. To identify novel compounds that can increase hepatic apo A-I production, two drug libraries were screened. The NIH clinical collection (NCC) and the NIH clinical collection 2 (NCC2) were purchased from Evotec (San Francisco, CA). The NCC library contains 446 compounds and the NCC2 library contains 281 compounds, all dissolved in dimethylsulfoxide at a concentration of 10 mM. Hepatoma-derived cells (HepG2) and primary hepatocytes in culture were treated with various compounds for 24 h and apo A-I in media samples was measured by enzyme immunoassay. Samples with significant changes in apo A-I concentrations were retested in independent experiments by Western blot analysis to confirm the immunoassay findings. Of a total of 727 compounds screened at a concentration of 50 µM, 15 compounds increased hepatic apo A-I production by 35%-54%, and 9 compounds lowered hepatic apo A-I concentrations in the culture media by 25%-52%. Future trials should explore the clinical effectiveness of these agents when standard doses of these drugs are used in humans.

25-Hydroxyvitamin D levels and acute cellular rejection in liver transplant patients.

OBJECTIVE: To investigate the association between 25-hydroxyvitamin D [25(OH)D] levels prior to liver transplantation (LT) and the development of acute cellular rejection (ACR) within the first year post LT. METHODS: This retrospective study included 275 consecutive LTs performed in 262 patients at Mayo Clinic in Jacksonville, Florida over 13 months. A total of 149 patients met the inclusion criteria. The correlations between 25(OH)D levels and the development, severity, and number of biopsy-proven ACR episodes were assessed. RESULTS: The prevalence of 25(OH)D levels <30 ng/mL was 92%. No association was found between pre LT 25(OH)D levels and the diagnosis of ACR (P = .61). Mean ± SD pre LT 25(OH)D levels were 16.1 ± 6.8 ng/mL for 48 subjects with no rejection, 16.1 ± 8.2 ng/mL for those with a mild first episode of ACR (n = 58), and 18.4 ± 12.4 ng/mL for those who experienced a moderate/severe first ACR (n = 39). However, in a subgroup analysis of patients with 25(OH)D levels <30 ng/mL, there was a statistically significant negative correlation (P = .0252) between 25(OH) D level and the ACR rate. CONCLUSION: Vitamin D insufficiency and deficiency prior to LT was prevalent in our cohort. There was no statistically significant association between low 25(OH)D levels and the diagnosis or severity of ACR or the number of rejection episodes within the first year post LT. However, there was a negative correlation between 25(OH)D levels below 30 ng/mL and the rate of ACR within 1 year post LT.