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*HISTAMINE
Endocrinology Vol. 138, No. 5 1863-1870
Copyright © 1997 by The Endocrine Society

Articles

Novel Effects of Histamine on Lipoprotein Metabolism: Suppression of Hepatic Low Density Lipoprotein Receptor Expression and Reduction of Plasma High Density Lipoprotein Cholesterol in the Rat1

Wei Liao, Mats Rudling and Bo Angelin

Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, and the Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden

Address all correspondence and requests for reprints to: Wei Liao, M.D., Ph.D., Department of Cell Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Histamine has been shown to be involved in atherosclerosis and coronary heart disease. Little information is available regarding the effects of histamine on lipoprotein metabolism. In the current study, we investigated the effects of histamine on the expression of hepatic low density lipoprotein (LDL) receptors and on plasma lipoproteins in the rat. Injection of compound 48/80 (C48/80, a histamine releaser) or histamine reduced hepatic LDL receptor expression, but not LDL receptor messenger RNA levels. Oral administration of polymyxin B (an antiendotoxin antibiotic and a histamine releaser) before the injection of C48/80 or histamine did not attenuate their effects. Polymyxin B itself had effects similar to those of C48/80 and histamine on LDL receptors. These results suggest that the effects of histamine are not mediated by the induction of gut-derived endotoxemia. Histamine H2 agonists (dimaprit and impromidine), but not H1 agonists (2-methylhistamine and 2-thiazolylethylamine), also reduced hepatic LDL receptor expression. The suppressive effect of C48/80 on hepatic LDL receptor expression was not attenuated by either the H1 antagonist (chlorpheniramine) or the H2 antagonist (cimetidine). Administration of C48/80 also reduced plasma high density lipoprotein (HDL) cholesterol. The H1 antagonist (chlorpheniramine), but not the H2 antagonist (cimetidine), almost completely reversed the effect of C48/80 on plasma HDL cholesterol. In conclusion, histamine suppresses hepatic LDL receptor expression via a non-H1 receptor-mediated pathway, and histamine reduces plasma HDL cholesterol via an H1 receptor-mediated pathway.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HISTAMINE is synthesized in mast cells and circulating basophils and stored within cellular secretory granules. Other cells can also synthesize histamine, but lack the capacity for histamine storage. The action of histamine is initiated by interaction with its specific receptors on the cells. Three histamine receptor subtypes, H1, H2, and H3, have been identified (1). The H1 and H2 receptors are widely distributed in many tissues, whereas the H3 receptor appears to be confined to the nervous system. In addition to its roles in allergic response and secretion of gastric acid and its action as a neurotransmitter (1), histamine has been implied to be involved in the development of atherosclerosis and coronary heart disease (2, 3, 4, 5, 6, 7, 8, 9). How histamine exerts such effects is not clear. An increased number of mast cells have been found in advanced atherosclerotic lesions as well as in the adventitia of the involved artery in patients with coronary spasm and associated vasospasm lesions (6, 8, 9). Histamine can provoke coronary arterial spasm (5) and increase the permeability of endothelial cells (7). Mast cells can also stimulate the uptake of low density lipoproteins (LDL) in macrophages and smooth muscle cells via their granule-mediated pathway, thereby leading to foam cell formation (10, 11, 12).

Elevated LDL cholesterol concentrations and reduced levels of high density lipoprotein (HDL) cholesterol are related to an increased risk of atherosclerosis. Hepatic LDL receptors play an important role in the regulation of the plasma LDL cholesterol level. Regulation of plasma lipoprotein levels may be another mechanism for how histamine influences the development of atherosclerosis. However, little information is available regarding the effects of histamine on lipoprotein metabolism. The effects on plasma cholesterol of antihistamines (H1 antagonists) (13, 14) and cimetidine (H2 antagonist) (15) suggest that histamine may play a regulatory role in lipoprotein metabolism. In the current study, we, therefore, investigated the effects of histamine on hepatic LDL receptor expression and plasma lipoproteins in the rat. We found that histamine suppresses hepatic LDL receptor expression and reduces plasma HDL cholesterol. This suggests that histamine may play an important role in lipoprotein metabolism, which may be related to its role in the development of atherosclerosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
Histamine (diphosphate salt; H 7375), compound 48/80 (C48/80; C 2313), polymyxin B sulfate (PMB; 7730 U/mg; P 1004), (±)-chlorpheniramine (maleate salt; C 3025), cimetidine (C 4522), and ranitidine (hydrochloride; R 0663) were purchased from Sigma Chemical Co. (St. Louis, MO). 2-Methylhistamine (dihydrochloride; SKF-91256-A2), 2-thiazolylethylamine (dihydrochloride; SKF-71481-A2), dimaprit (dihydrochloride; SKF-91441-A2), and impromidine (trihydrochloride; SKF-92676-A3) were provided by SmithKline Beecham Pharmaceuticals (The Frythe, Welwyn, Herts AL6 9AR, UK).

Animals and experimental procedure
Male Sprague-Dawley rats (~250 g) were maintained under standardized conditions with free access to chow and water. The light cycle was between 0600–1800 h. Animals were allowed to adapt to the environment for at least 1 week before starting the experiments. All protocols were approved by the institutional animal care and use committee.

One hundred and fifty six rats were used in seven separate experiments. In all experiments each group consisted of six animals. Animals were fasted overnight (starting about 1500 h). At 0900 h on the following day, if not otherwise stated, rats were injected sc with C48/80 (2 mg/rat) or ip with histamine (0.065 mmol/kg BW; i.e. 20 mg/kg BW) or histamine agonists (0.065 mmol/kg BW; i.e. 13 mg for 2-methylhistamine and 2-thiazolylethylamine, 15 mg for dimaprit, 28 mg for impromidine/kg BW). Sterile saline was used as vehicle; control rats received saline. The dose of C48/80 was chosen as that inducing a typical allergic reaction (16), and the dose of histamine was that inducing a maximal gastric acid secretion (17). Six hours after the injection (i.e. at 1500 h), rats were anesthetized with ether, and blood was taken into EDTA-containing tubes (Vacutainer, Becton Dickinson, Meylan Cedex, France) by puncture of the abdominal aorta. Animals were then killed by cervical dislocation, and the livers were removed, immediately frozen in liquid nitrogen, and later stored at -70 C. In some experiments, PMB, chlorpheniramine, cimetidine, and ranitidine were given orally through a stomach tube using saline as vehicle. While the groups of animals were given these drugs orally, other groups of animals received the same volume of saline. PMB was given at a dose of 4.8 mg (~37,000 U)/kg BW twice, 1 and 13 h before the injection of C48/80 or histamine. Chlorpheniramine (H1 antagonist), cimetidine, and ranitidine (H2 antagonists) were given at approximately a 10-fold dose (on a molar basis) of histamine or histamine agonists, i.e. 0.6 mmol/kg BW (233, 150, and 209 mg/kg BW for chlorpheniramine, cimetidine, and ranitidine, respectively) 1 h before the injection of C48/80 or histamine agonists. After receiving C48/80, the animals developed a typical allergic skin reaction, i.e. marked edema or erythema of snoots, ears, and paws, which occurred about 3 h and peaked about 6 h postinjection. No diarrhea occurred in C48/80-, histamine-, or histamine agonist-treated animals.

Plasma lipid determination and size fractionation of lipoproteins
Plasma total cholesterol and triglycerides were assayed individually in duplicate using commercial kits (Boehringer Mannheim, Mannheim, Germany). Size fractionation of lipoproteins was performed on the pooled plasma samples of each group by fast protein liquid chromatography (FPLC) (18, 19). Equal volumes of plasma from every rat in each group were pooled (5 ml), and the density was adjusted to 1.21 g/ml with solid potassium bromide. After ultracentrifugation at 100 x 103 g for 48 h, the supernatant (lipoprotein fraction) was removed and adjusted to 2 ml by adding FPLC elution solution (0.15 M NaCl, 0.01% EDTA, and 0.02% sodium azide, pH 7.3). After filtration through a 0.45-µm filter, 1 ml of the supernatant (corresponding to 2.5 ml plasma) was injected onto a 54 x 1.8-cm Superose 6B column. Fractions of 2 ml were collected, and total cholesterol and triglycerides were measured.

Preparation of hepatic membranes and ligand blot assay of LDL receptors
Hepatic membranes were prepared from the pooled liver samples (0.5 g) of each group as previously described (20). The liver samples were homogenized with a Polytron (Kinematica, type PT 10/35, Kriens, Lucerne, Switzerland) at 4 C in 1 ml buffer (2 mM CaCl2, 0.5% Triton X-100, 1 mM leupeptin, 1 mM phenanthroline, 1 mM phenylmethylsulfonylfluoride, and 50 mM Tris-HCl, pH 7.5). After quick sonication, homogenates were centrifuged for 10 min (4 C, 14,000 rpm) in a microcentrifuge, followed by 7-min ultracentrifugation at 30 psi (206.7 kPa) in a Beckman Airfuge at room temperature (Palo Alto, CA), using a prechilled ice-cold rotor. The supernatant was collected and assayed for protein (21), using reagents from Bio-Rad (Richmond, CA). The membrane preparation was mixed with loading buffer (10% glycerol, 0.5% SDS, 2 mM CaCl2, 0.5% Triton X-100, 0.05% bromophenol blue, and 50 mM Tris-HCl, pH 6.8). For each group, 50, 100, and 200 µg membrane protein/lane were loaded on the gel and separated under nonreduced conditions on 6% SDS-polyacrylamide gels, then electrotransferred onto 0.45-µm nitrocellulose filters (type BA 85, Schleicher and Schuell, Keene, NH). After 1-h preincubation in 5% BSA, 2 mM CaCl2, 1 mM KI, and 50 mM Tris-HCl, pH 8.0, the filters were incubated for 1 h with 125I-labeled rabbit ß-migrating very low density lipoprotein (VLDL; 5 µg/ml). Filters were washed with 0.5% BSA, 2 mM CaCl2, and 50 mM Tris-HCl, pH 8.0, and thereafter with the washing buffer without albumin. Filters were exposed to Kodak XAR film (Eastman Kodak, Rochester, NY). LDL receptor expression in blots was quantitated using a Bio-Imaging Analyzer (Fujix, BAS 2000, Fuji Photo Film Co., Ltd. Tokyo, Japan). Background levels measured in irrelevant filter areas of the same size were subtracted from the data presented.

Total nucleic acid (TNA) preparation and analysis of LDL receptor messenger RNA (mRNA)
TNA was prepared according to the method of Durnam and Palmiter (22). Liver samples from each individual were homogenized with a Polytron in 4 ml buffer (1% SDS, 10 mM EDTA, and 20 mM Tris-HCl, pH 7.5) and digested for 45 min at 45 C with proteinase K (200 µg/ml). TNA was precipitated by adding 2 vol pure ethanol after phenol-chloroform extraction, and the pellet was suspended in the buffer. Quantitation of LDL receptor mRNA was performed by a solution hybridization titration assay using a mouse [35S]UTP complementary RNA probe (19). The slopes of the linear hybridization signals were calculated by the method of least squares and compared with the slope generated from a synthetic mouse LDL receptor mRNA standard. Data are expressed as attomoles (amol) per µg TNA.

Statistics
Data are presented as the mean ± SEM and analyzed using Statistica software (StatSoft, Tulsa, OK). One-way ANOVA was used to evaluate the presence of significant differences between groups, followed by post-hoc comparisons of the group means according to the method of Tukey.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of endogenous histamine
We used C48/80 to induce the release of endogenous histamine (23). Rats were injected with C48/80 6 and 24 h before killing the animals. Six hours postinjection, hepatic LDL receptor expression was reduced by 65%, and after 24 h, it was still lower (by 19%) than that in the control group (Fig. 1Go, A and B). However, there was no reduction in LDL receptor mRNA after the injection of C48/80 (Fig. 1BGo). Plasma total cholesterol was decreased by 25% at 6 h (P < 0.01), whereas it was not significantly lower than the control value 24 h postinjection (Fig. 1CGo). Plasma triglycerides were unchanged after the injection of C48/80. To characterize the plasma lipoprotein changes, lipoproteins were separated by FPLC. Clearly, C48/80 decreased plasma cholesterol by reducing HDL cholesterol, whereas LDL cholesterol was unchanged (Fig. 1DGo). Triglycerides were slightly decreased in VLDL, but increased in LDL and intermediate density lipoproteins (IDL) (Fig. 1EGo).



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  		Figure 1. Effects of C48/80 on hepatic LDL receptor expression and plasma lipoproteins. Groups of rats were injected with C48/80 (2 mg/rat) 6 or 24 h before they were killed. Control rats received an equal volume of vehicle 24 h before they were killed. Livers were obtained for the determination of LDL receptor expression and LDL receptor mRNA levels, and blood was drawn for analyses of plasma total cholesterol and triglycerides and for FPLC analysis of plasma lipoproteins. Cholesterol and triglycerides in plasma and LDL receptor mRNA were determined individually. A ligand blot assay of LDL receptor and a FPLC analysis of plasma lipoproteins were performed on the pooled samples of each group. A, Ligand blot assay of LDL receptor. For each group, 50, 100, and 200 µg membrane protein/lane (from left to right) were loaded. The molecular mass is indicated in kilodaltons on the left side of the figure. B, Quantitation of LDL receptor expression and LDL receptor mRNA. C, Plasma cholesterol and triglyceride levels. D, FPLC lipoprotein cholesterol pattern. E, FPLC lipoprotein triglyceride pattern. *, P < 0.01 compared with control.

 
As histamine may induce gut-derived endotoxemia (16, 24), and as endotoxin can suppress hepatic LDL receptor expression (25) and reduce plasma HDL cholesterol (26, 27), it is possible that histamine suppressed hepatic LDL receptor expression and reduced plasma HDL cholesterol through the induction of gut-derived endotoxemia. To test this, PMB was used in the following experiment. PMB has antiendotoxin properties (28) and is also a histamine releaser (29, 30). PMB was given orally twice, 1 and 13 h before the injection of C48/80. In this experiment, C48/80 alone suppressed hepatic LDL receptor expression by 74% (Fig. 2Go, A and B) and decreased plasma total cholesterol by 23% (P < 0.002; Fig. 2CGo) due to a reduced HDL cholesterol level (Fig. 2DGo), confirming the above findings. PMB did not attenuate the effects of C48/80 on hepatic LDL receptor expression (Fig. 2Go, A and B) or on plasma (HDL) cholesterol (Fig. 2Go, C and D). However, PMB alone suppressed hepatic LDL receptor expression by 52% (Fig. 2Go, A and B) and tended to decrease plasma cholesterol (by 14%; Fig. 2CGo) by reducing HDL cholesterol levels (Fig. 2DGo), which were similar to although less pronounced than the effects of C48/80. These results suggest that the effects of C48/80 were not mediated by the induction of gut-derived endotoxemia. Although C48/80, PMB, or their combination markedly reduced hepatic LDL receptor expression, these treatments did not decrease LDL receptor mRNA levels (Fig. 2BGo).



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  		Figure 2. Influence of PMB on the effect of C48/80 on hepatic LDL receptor expression and plasma lipoproteins. PMB was given twice at a dose of 4.8 mg/kg BW, 1 and 13 h before the injection of C48/80. Six hours after the injection of C48/80 (2 mg/rat), livers and blood were obtained for the determination of LDL receptor expression, LDL receptor mRNA levels, and plasma lipids as described in Fig. 1Go. *, P < 0.002; {dagger}, P < 0.001 (compared with control).

 
Effects of exogenous histamine
We also studied whether exogenous histamine could have effects similar to those of histamine releaser. Six hours after histamine injection, hepatic LDL receptor expression was reduced by 43% (Fig. 3Go, A and B), whereas LDL receptor mRNA was not decreased (Fig. 3BGo). Histamine also tended to reduce plasma total cholesterol (by 17%; Fig. 3CGo). This reflected a diminished HDL cholesterol level (Fig. 3DGo). There was no change in LDL cholesterol. Histamine seemed to increase VLDL triglyceride levels (Fig. 3EGo). PMB given orally twice before the injection of histamine did not attenuate the effects of histamine on hepatic LDL receptor expression and plasma total and HDL cholesterol. Thus, the combination of PMB and histamine suppressed hepatic LDL receptor expression by 61% (Fig. 3Go, A and B) and decreased plasma total cholesterol by 23% (P = 0.05; Fig. 3CGo) due to a reduced HDL cholesterol level (Fig. 3DGo). These results further support the idea that the effects of histamine are not mediated by the induction of gut-derived endotoxemia.



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  		Figure 3. Influence of PMB on the effect of exogenous histamine on hepatic LDL receptor expression and plasma lipoproteins. PMB was given twice at a dose of 4.8 mg/kg BW, 1 and 13 h before the injection of histamine. Six hours after the injection of histamine (0.065 mmol/kg BW), livers and blood were obtained for the determination of LDL receptor expression, LDL receptor mRNA levels, and plasma lipids as described in Fig. 1Go. *, P = 0.05 compared with control.

 
Effects of histamine agonists and antagonists
To determine through which receptor histamine suppressed hepatic LDL receptor expression and reduced plasma HDL cholesterol, H1 and H2 agonists were used. 2-Methylhistamine and 2-thiazolylethylamine (H1 agonists) did not suppress, but seemed to stimulate, hepatic LDL receptor expression (Fig. 4Go, A and B). On the other hand, dimaprit and impromidine (H2 agonists) suppressed hepatic LDL receptor expression by 25% and 30%, respectively (Fig. 5Go, A and B). At the dose used, H1 agonists tended to decrease HDL cholesterol (Fig. 4DGo), whereas H2 agonists did not decrease cholesterol in this lipoprotein fraction (Fig. 5DGo). VLDL triglyceride levels also decreased after administration of H2 agonists.



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  		Figure 4. Effects of H1 agonists on hepatic LDL receptor expression and plasma lipoproteins. Groups of rats were injected with H1 agonists (0.065 mmol/kg BW), 2-methylhistamine (2-MH) or 2-thiazolylethylamine (2-TL). Six hours after the injection of H1 agonists, livers and blood were obtained for the determination of LDL receptor expression and plasma lipids as described in Fig. 1Go.

 


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  		Figure 5. Effects of H2 agonists on hepatic LDL receptor expression and plasma lipoproteins. Groups of rats were injected with H2 agonists (0.065 mmol/kg BW), dimaprit (DMP) or impromidine (IMP). Six hours after the injection of H2 agonists, livers and blood were obtained for the determination of LDL receptor expression and plasma lipids as described in Fig. 1Go.

 
H1 and H2 antagonists were then given to C48/80-treated rats to establish whether they could block the effects of C48/80 on hepatic LDL receptor expression and plasma HDL cholesterol. Chlorpheniramine (H1 antagonist) and cimetidine (H2 antagonist) were orally administered 1 h before the injection of C48/80. In this experiment, C48/80 alone suppressed hepatic LDL receptor expression by 63% (Fig. 6Go, A and B) and decreased plasma cholesterol by 25% (P < 0.001; Fig. 6CGo) due to a reduced HDL cholesterol level (Fig. 6DGo). Chlorpheniramine and cimetidine only slightly suppressed hepatic LDL receptor expression (data not shown). Chlorpheniramine had no effect on plasma cholesterol or the lipoprotein cholesterol pattern, but reduced plasma triglyceride levels by 43% (P < 0.001) due to a decreased VLDL triglyceride level; cimetidine tended to reduce plasma HDL cholesterol levels (data not shown). Neither chlorpheniramine nor cimetidine could block the suppressive effect of C48/80 on hepatic LDL receptor expression (Fig. 6Go, A and B). However, chlorpheniramine almost completely reversed the effect of C48/80 on plasma HDL cholesterol, whereas cimetidine had no effect (Fig. 6Go, C and D). In a separate experiment, we studied whether H2 antagonists could block the inhibitory effect of impromidine (H2 agonist) on hepatic LDL receptor expression. In this experiment, hepatic LDL receptor expression was reduced by 30% 6 h after the injection of impromidine (0.065 mmol/kg BW). However, the suppressive effect on LDL receptors could not be blocked by prior oral administration of cimetidine or ranitidine (0.6 mmol/kg BW; data not shown).



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  		Figure 6. Influence of histamine antagonists on the effect of C48/80 on hepatic LDL receptor expression and plasma lipoproteins. Chlorpheniramine (CPR; H1 antagonist) or cimetidine (CTD; H2 antagonist) were orally administered at a dose of 0.6 mmol/kg BW 1 h before the injection of C48/80 (2 mg/rat). Six hours after the injection of C48/80, livers and blood were obtained for the determination of LDL receptor expression and plasma lipids as described in Fig. 1Go. *, P < 0.001 compared with control; {dagger}, P < 0.01 compared with C48/80, but no significant difference compared with control; {ddagger}, P < 0.01 compared with control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study shows that histamine, of endogenous or exogenous origin, suppresses hepatic LDL receptor expression and reduces plasma HDL cholesterol, suggesting an important role of histamine in the regulation of lipoprotein metabolism. To our knowledge, histamine is the only hormone shown to have a suppressive effect on hepatic LDL receptor expression in vivo. Various hormones and cytokines stimulate LDL receptors, such as estrogen, insulin, insulin-like growth factor I, thyroid hormone, glucagon, adrenaline, platelet-derived growth factor, tumor necrosis factor, interleukin-1 and -6, oncostatin M, and transforming growth factor-ß (20, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44). Hormones, thus, play important roles in the regulation of LDL receptors (45), and the model of histamine treatment may provide an important new system to further understand this regulation.

Evidence of posttranscriptional regulation of LDL receptors has been shown in vitro and in vivo (31, 46). In the present study, we showed that administration of histamine or histamine releasers (C48/80 and PMB) to rats suppressed hepatic LDL receptor expression without reducing LDL receptor mRNA, suggesting that histamine suppresses hepatic LDL receptor expression beyond the level of transcription. Thus, the present findings further support the concept of a posttranscriptional regulation of hepatic LDL receptors.

As histamine may induce gut-derived endotoxemia (16, 24), and endotoxin can also suppress hepatic LDL receptor expression (25) and reduce plasma HDL cholesterol (26, 27), it is possible that histamine suppressed hepatic LDL receptor expression and reduced plasma HDL cholesterol through the induction of gut-derived endotoxemia. We have tried to exclude this possibility by using PMB. Besides its antimicrobial activity, PMB has antiendotoxin properties (28), as it binds to the lipid A part of endotoxin; PMB itself is also a histamine releaser (29, 30). PMB was administered orally for targeting the intestinal endotoxins and for avoiding the systemic toxicity of PMB. This treatment also avoids the possible interaction of PMB with plasma lipoproteins, as PMB is known to interact with lipoproteins to form complexes (47, 48). Oral administration of PMB has been shown to rapidly eliminate endotoxemia in patients with liver cirrhosis (49) and sepsis (50). Although the dose used in the present study was high compared to that used in those studies, PMB treatment before the injection of C48/80 or histamine did not attenuate their effects on hepatic LDL receptor expression or plasma HDL cholesterol. Accordingly, there were no signs of endotoxemia in the animals that received C48/80 or histamine, and diarrhea and hypertriglyceridemia, the known responses to endotoxin in vivo (51, 52, 53), were not present in these animals. These results suggest that the effects of histamine are not mediated by gut-derived endotoxemia. However, more data are required to verify this. Studies of the effects of histamine in the germ-free (thus endotoxin-free) animals and in the animals with specific deletion of the structural proteins (such as CD14 and lipopolysaccharide-binding protein) in the endotoxin signal transduction pathway may provide additional evidence. On the other hand, similar to C48/80, PMB, being a histamine releaser, suppressed hepatic LDL receptor expression and tended to reduce plasma HDL cholesterol. This further strengthens the idea that histamine suppresses hepatic LDL receptor expression and reduces plasma HDL cholesterol.

The H1 receptor is not involved in the histamine-induced suppression of hepatic LDL receptor expression. Thus, H1 agonists did not reduce hepatic LDL receptor expression, and chlorpheniramine (H1 antagonist) almost completely reversed the effect of histamine on plasma HDL cholesterol, but did not block the suppressive effect of histamine on hepatic LDL receptor expression. In contrast, H2 agonists reduced hepatic LDL receptor expression, suggesting that histamine probably suppresses hepatic LDL receptor expression via an H2 receptor pathway. However, H2 antagonists (cimetidine and ranitidine) could not block the suppressive effect of C48/80 and H2 agonist (impromidine) on hepatic LDL receptor expression. The reason for this unexpected finding is unclear. It might imply that the dose of H2 antagonists used was too low. However, the amounts administered in the present study are 10-fold higher (on a molar basis) than those of histamine or histamine agonists. H2 antagonists are rapidly and well absorbed after oral administration, with peak levels attained in plasma within 1–2 h; the half-life for the elimination of cimetidine and ranitidine is 2–3 h (54). Thus, it is unlikely that the inability of H2 antagonists to block the effects of C48/80 or impromidine on hepatic LDL receptor expression was due to inadequate plasma concentrations. Rather, the inability of H2 antagonists to block the suppressive effect of C48/80 and impromidine on LDL receptors might reflect the possibility that H2 antagonists interfere little with effects other than physiological regulation of gastric acid secretion (54). Alternatively, it may suggest the existence of a new, unidentified histamine receptor that recognizes H2 agonists but not H2 antagonists. Further studies are needed to clarify the details of this potentially important receptor-mediated pathway by which histamine suppresses hepatic LDL receptor expression.

The mechanism(s) responsible for the effects of histamine on hepatic LDL receptors can only be speculated upon. Histamine-induced suppression of LDL receptor might be a consequence of increased uptake of the cholesterol-enriched lipoproteins, LDL and HDL. FPLC analysis of lipoprotein profiles showed in the present study that there was no clear change in LDL cholesterol after the administration of histamine or histamine releaser. It could also be possible that histamine stimulates HDL cholesterol uptake by the liver, resulting in a secondary down-regulation of LDL receptors. It is not known whether histamine-induced reduction of HDL cholesterol is due to an increased HDL uptake or a decreased HDL secretion. However, histamine-induced suppression of LDL receptor is not secondary to a reduction of plasma HDL cholesterol, because the H1 antagonist (chlorpheniramine) almost completely reversed the reducing effect of C48/80 on HDL cholesterol, but did not block its effect on LDL receptor. Furthermore, regulation of the LDL receptor by sterol accumulation is generally transcriptional and we did not observe any reduction in LDL mRNA in response to histamine.

Clearly, histamine reduced plasma HDL cholesterol through an H1 receptor-mediated pathway, because the effect of C48/80 on plasma HDL cholesterol was reversed by prior administration of chlorpheniramine (H1 antagonist), but not cimetidine (H2 antagonist). However, the mechanism for this is unknown. Stimulation of H1 receptor may increase HDL uptake by the liver or inhibit apolipoprotein A-I (and HDL) secretion, thereby leading to a reduction of HDL cholesterol. Further studies are needed to directly address this interesting question.

Histamine and histamine releasers clearly reduced hepatic LDL receptor expression, but they did not induce changes in plasma LDL cholesterol. The reason for this is not understood. The fact that the normal lipoprotein profile in rats is different from that in humans, with a predominant HDL fraction and very minor LDL peak, may be one explanation for this. A study in cholesterol-fed rats (in which IDL-LDL cholesterol is increased) or other animal models with a typical LDL (such as hamsters) may be more revealing of the potential effect of histamine on LDL cholesterol levels.

Exogenous histamine or PMB had only a partial effect compared to C48/80. This may reflect different pharmacokinetics and administration routes of these drugs. Histamine is rapidly cleared after injection (30). In the present study, PMB was given orally, whereas C48/80 was injected sc. After oral administration, little PMB is absorbed from intestine.

In conclusion, histamine suppresses hepatic LDL receptor expression via a non-H1 receptor-mediated pathway, and histamine reduces plasma HDL cholesterol via an H1 receptor-mediated pathway.


   Acknowledgments
 
We thank S. Trowbridge, P. G. Treagust, and P. Bartlett (SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR, UK) for kindly providing and handling histamine agonists, and L. Larsson for the preparation and labeling of rabbit ß-VLDL.


   Footnotes
 
1 This work was supported by grants from the Karolinska Institute; the Swedish Medical Council (03X-7137); the Swedish Society of Medicine (565.0 and 619.0); the Thuring, Widengren, Jeansson, and Lundström Foundations; and the Ruth and Richard Julin, the Old Female Servants, the Ax:son Johnson, and the Nordic Insulin Funds. Back

Received September 26, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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