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  • Recent studies in our laboratory demonstrated that several


    Recent studies in our laboratory demonstrated that several histamine H1 receptor antagonists induce apo A-I gene expression while histamine itself represses it [20]. In humans, there are three histamine receptor genes (H1, H2, and H3) that code for G-protein-coupled receptors (GPCR's) which bind histamine with high-affinity and stimulate various intracellular signaling pathways [21]. H1 and H2 histamine receptors are expressed in hepatocytes [22], however there are only a few reports regarding their potential roles in modulating hepatic function. Rokita et al. [23] demonstrated that histamine was essential in priming murine hepatocytes to express genes involved in the acute phase response when treated with interleukin 6 (IL-6). The response required the histamine H1 receptor but not the histamine H2 receptor. Histamine was also shown to increase IL-6 binding in CESS B cell lymphoma cells, but decreased IL-6 binding in HepG2 hepatocytes and U937 monocytoid cells [24]. Interestingly, increased IL-6 binding in the B-cell lymphoma cells was dependent on the histamine H1 receptor, while the histamine H2 receptor was essential for the effects of histamine in HepG2 cells as well as the monocytoid cells. A third histamine H1 receptor antagonist/serotonin receptor antagonist, cyproheptadine, was recently shown to induce calcitonin gene related peptide arrest of HepG2 and Huh-7 hepatocytes, in part by inducing expression of the cell cycle regulators HMG-box transcription factor 1, p16, p21, and p27 [25]. It is also important to point out that mast cell activation is heavily influenced by local factors and that pathways that modulate mast cell activity in the liver and atherosclerotic plaque should be examined independently. Though mast cells and histamine have been shown to have a potentially important role in the early and late stages of atherosclerosis within the atherosclerotic plaque, especially in plaque destabilization [26, 27], there is little evidence in the literature to suggest that histamine has effects on other major risk factors for ASCD, including lipoprotein, cholesterol, and triglyceride levels. Fexofenadine was shown however to increase HDL-C levels in rats while histamine reduced plasma HDL-C levels and suppressed LDL-C receptor expression [28]. Further support for a role of histamine in promoting atherogenesis came from a study in apoE−/− mice in which antihistamines were shown to inhibit atherosclerosis in mice fed a high-fat diet for three months [29]. These studies clearly provide support for the idea that histamine may have an underappreciated role in promoting atherosclerosis. Since we recently reported that various antihistamines induce apo A-I gene expression [20], we wanted to examine the role of the histamine receptors in regulating apo A-I gene expression. In the presence of histamine, the H1 histamine receptor stimulates several intracellular signaling pathways, including nuclear factor-κB (NF-κB) activity [30, 31]. Since NF-κB has been shown to repress apo A-I gene expression in lipopolysaccharide-treated hepatocytes [32], we wished to determine whether NF-κB is involved in regulating apo A-I gene expression in HepG2 hepatoma derived cells.
    Materials and methods
    Discussion There is robust evidence supporting a role for mast cells and histamine in atherosclerosis [23, 24, 41], including evidence that certain contents from mast cells, in particular chymase, tryptase, and histamine, promote dyslipidemia. Incubation of the HDL3 fraction with exocytosed mast cell granules led to substantial degradation of apo A-I with the preferred substrate being preβ-HDL [42, 43]. This loss of preβ-HDL, the high-affinity substrate for cholesterol efflux by ABCA1, reduced its cholesterol efflux capacity [44]. Furthermore, mast cell granule proteoglycans have been shown to interact with and stabilize chymase and tryptase, increasing their ability to degrade HDL within the atherosclerotic plaque [45, 46]. Histamine, in contrast, may have a role in suppressing atherosclerosis due to its ability to increase endothelial cell permeability, potentially elevating the interstitial pool of HDL-C in the atherosclerotic lesion, promoting macrophage-dependent reverse-cholesterol transport [47]. We recently observed that histamine represses apo A-I gene expression while treatment with various histamine H1 receptor antagonists increased apo A-I gene expression [20]. Treatment with histamine lowered apo A-I protein and mRNA levels, as well as repressed apo A-I reporter gene expression [20]. Furthermore, treatment with histamine H1 receptor antagonists including diphenhydramine and loratidine induced apo A-I expression while histamine H2 receptor antagonists had no effect [20]. Based on these observations, we expanded our investigation to determine whether or not histamine regulates apo A-I gene expression via modulation of histamine H1 receptor and NF-κB in HepG2 cells.