Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats

Jianmin Ran, Tsutomu Hirano, and Mitsuru Adachi

First Department of Internal Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan

Submitted 5 May 2004 ; accepted in final form 15 June 2004


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We recently observed that ANG II receptor blocker therapy improved the overproduction of triglyceride (TG) in fructose-fed rats and Zucker fatty rats with insulin resistance, which in turn suggests that ANG II may stimulate TG production. Accordingly, we investigated the effects of ANG II on TG production and the association with insulin resistance in normal rats. Male Wistar rats were continuously infused with ANG II (100 ng·min–1·kg body wt–1) via an osmotic minipump for 14 days. ANG II infusion markedly elevated both the systolic and diastolic blood pressure. The plasma TG level increased twofold, but cholesterol was unchanged. ANG II infusion stimulated the TG secretion rate (TGSR) by twofold and increased the hepatic TG content by 31%. Lipogenesis determined by [2-3H]glycerol incorporation into hepatic TG was also significantly increased in ANG II-infused rats. The stimulatory effect of ANG II on TGSR was dose dependent and was not observed until 2 wk after the start of infusion. ANG II infusion significantly reduced insulin sensitivity index (SI) without affecting glucose effectiveness determined by Bergman's minimal model. The plasma TG level was positively correlated with TGSR (r = 0.88, P < 0.001) and inversely with SI (r = –0.80, P < 0.005). These results suggest that chronic ANG II infusion stimulates hepatic TG production, which is partly associated with simultaneous development of insulin resistance. Our results may suggest a new mechanism for the intimate association between hypertension and dyslipidemia.

angiotensin II; triglyceride metabolism; insulin resistance; liver; rat


GLUCOSE INTOLERANCE, hypertension, and dyslipidemia, a triad of established risk factors for cardiovascular diseases, are often clustered in individuals with insulin resistance and its compensatory hyperinsulinemia. Although hypertension is associated with glucose intolerance or dyslipidemia, the exact mechanisms behind these associations remain largely unknown. ANG II, a potent vasoconstrictor, plays an important role in the development of hypertension (20), and there has been accumulating evidence that ANG II directly impairs insulin action (33, 35, 29). In turn, there are several studies that have demonstrated that ANG I converting-enzyme inhibitors, or ANG II type 1 receptor blockers (ARBs), can improve insulin resistance (16, 13). Hypertriglyceridemia is a major component of this insulin-resistant syndrome (37). It is well recognized that insulin resistance/hyperinsulinemia stimulates the hepatic production of very-low-density lipoproteins, a major carrier protein of endogenously produced TG (26). Therefore, it is reasonable to assume that ARB suppresses the TG overproduction associated with insulin resistance. Indeed, we recently observed that an ARB, olmesartan medoxomil, suppresses TG overproduction in fructose-fed rats (30) and Zucker fatty rats (32), both of which are representative animal models of insulin resistance. These results in turn led us to speculate that ANG II can stimulate hepatic TG production. Several in vitro experiments have demonstrated that ANG II stimulates lipogenesis in adipocytes (20, 24) or cholesterogenesis in macrophages(23), which also suggests a potential ability of ANG II on stimulating TG production in the liver. Therefore, we examined how the administration of exogenous ANG II administration alters the plasma TG concentration and hepatic TG production in rats, as well as the association of TG metabolism with the corresponding insulin resistance. This study may provide a new mechanism for explaining the close relationship between hypertension and dyslipidemia.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Eight-week-old male Wistar rats (Charles River Japan) were fed standard stock diet containing 60% vegetable starch, 5% fat, and 24% protein (Oriental Yeast, Tokyo, Japan). Human ANG II (A-9525; Sigma, St. Louis, MO) was continuously infused at 100 ng·min–1·kg body wt–1 (BW) for 14 days by an osmotic minipump (Alzet model 1007D) that was implanted subcutaneously (n = 12; see Ref. 29). In control rats (n = 10), saline was infused via the same type of minipump. In other rats, 10 or 50 ng·min–1·kg–1 (n = 8 for each infusion rate group) of ANG II were infused for 14 days, and ANG II (100 ng·kg–1·min–1) or saline (n = 6 for each group) was infused for 7 days. All rats were housed individually in cages in a room with a 12:12-h light-dark cycle and had free access to food and water. On the day of the experiment, food was removed at 9:00 AM, but water was always available. The experiment was started at 2:00 PM after a 5-h fast. All procedures were proved by the Institutional Animal Care and Use Committee of Showa University according to the guidelines for the Care and Use of Laboratory Animals.

Measurement of blood pressure and heart rate. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded in conscious rats using indirect tail-cuff equipment (Natsume Seisakusho, Tokyo, Japan). Rats were warmed at 37°C on a warming plate for 20 min, the blood pressure (BP) or HR was measured five times each, and mean values were calculated as the individual BP or HR.

Triglyceride secretion rate. The triglyceride secretion rate (TGSR) was determined by the Triton WR-1339 method, as described in detail previously (14, 37). Rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg), and 600 mg/kg Triton WR-1339 (Sigma) were injected intravenously. Blood samples were taken before and 60 and 90 min after injection. TGSR was calculated from the increment of the plasma triglyceride (TG) concentration per minute multiplied by the plasma volume (estimated as 4% body wt; see Refs. 14 and 37) and was expressed as milligrams per minute per 100 g body wt. We confirmed that Triton WR-1339 (600 mg/kg) completely inhibited TG removal for at least 90 min after injection (36). Thus any increment of plasma TG after Triton WR-1339 injection was attributable to newly secreted TG, mainly produced by the liver. Because the rats were fasted for 5 h before the experiment, the intestinal contribution to the TGSR was assumed not to be significant (4).

Hepatic lipid content. Livers were removed after the final blood sampling was obtained in the Triton study or the frequent sampling intravenous glucose tolerance test (FS-IVGTT). In preliminary studies, we confirmed that the injection of Triton WR-1339 or glucose did not affect the hepatic lipid content (data not shown). Dissection of the liver was done after infusion of a large volume of saline in the portal vein to wash out all blood, and the tissues were placed in liquid nitrogen immediately. Total lipids were extracted from hepatic tissues according to the method of Bligh and Dyer (5). Briefly, 1.25 g of tissue were homogenized with 3.75 ml of chloroform-methanol (1:2 vol/vol) using a hand-held Polytron homogenizer (PT10/35). After vigorous vortexing for 15 min, 1.25 ml each of chloroform and water were added and mixed sequentially, and then the mixture was briefly centrifuged at 3,000 rpm to separate the phases. The lower phase was transferred to another tube, and the residue was mixed with 1.88 ml of chloroform, followed by repeat vortex and centrifugation. Next, the lower phase was mixed with the first chloroform phase in the same tube and evaporated under nitrogen gas at 55°C. Finally, the lipid extract was dissolved in 2 ml of 2-propanol. TG and cholesterol levels were assayed by enzymatic methods, as described below.

[2-3H]glycerol incorporation into hepatic TG for lipogenesis measurement. [2-3H]glycerol (7.4 x 105 Bq; New England Nuclear, Boston, MA) was injected in the femoral vein in rats infused with saline (n = 5) and ANG II (100 ng·kg–1·min–1; n = 5) for 2 wk. The liver was removed 30 min after the injection under pentobarbital anesthesia, and total lipids were extracted from the liver by the same procedure described above. TG was separated by TLC using a polyester-backed silica gel TLC plate (Kieselgel 60; Merck), which was developed in a solvent phase containing petroleum ether-diethyl ether-glacial acetic acid (80:20:1, vol/vol/vol). Lipid fraction was visualized by incubation in iodine vapor, and the TG layer was cut and quantified by liquid scintillation. Liver TG radioactivity and TG specific activity were expressed as disintegrations per minute per gram liver and disintegrations per minute per milligram liver TG, respectively.

FS-IVGTT. The FS-IVGTT was performed to evaluate the insulin sensitivity index (SI) and glucose effectiveness (SG) by Bergman's (3) minimal model method. Briefly, 50% glucose solution (0.5 g/kg) was injected as a bolus, and blood samples (0.15 ml of blood each time) were taken at –5, 0, 2, 4, 6, 8, 10, 12, 14, 16, 19, 22, 30, 40, 60, 90, and 120 min. The areas under the curve of glucose (AUCG) and insulin (AUCI) were calculated by the intrapezoid method. SI and SG, two parameters that represent insulin-dependent and glucose-dependent glucose disposal in vivo, respectively (3), were mathematically estimated as described in detail previously (28). The plasma glucose disappearance rate constant (Kg) was calculated as the slope of the least-square regression line relating the natural logarithm of the glucose concentration between 4 and 16 min (28).

Biochemical assays. Glucose, total cholesterol (TC), TG, nonesterified fatty acids (NEFA), and high-density lipoprotein-cholesterol (HDL-C) were measured in duplicate by spectrophotometry with standard commercial kits (Wako Pure Chemical Industries, Osaka, Japan). Plasma insulin concentration was determined using a specific insulin ELISA kit for rats (Morinaga, Yokohama, Japan).

Statistical analysis. Results are expressed as means ± SD. Student's t-test, one-way ANOVA, and Tukey's post hoc analysis were used to evaluate differences of mean values. Correlation coefficients were assessed by Pearson's simple-correlation analysis. Statistical significance was accepted at P < 0.05.


    RESULTS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
General profiles after infusion of ANG II for 2 wk with different infusion rates. Different doses of ANG II infusion did not affect the body weight, or food and water consumption. After infusion of ANG II for 14 days, both SBP and DBP were significantly elevated at a low rate (10 ng·min–1·kg–1) and were further increased at 50 ng·min–1·kg–1, although plateau was seen at a higher infusion rate (100 ng·min–1·kg–1), whereas HR was left unchanged (Table 1). The plasma glucose level was not affected by different infusion rates, but the plasma insulin level was significantly increased with the ANG II infusion. However, the insulin level was not affected by the rate of the ANG II infusion.


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Table 1. General profiles in rats infused with saline or different doses of ANG II for 2 wk

 
Both plasma TG and NEFA levels increased with ANG II infusion in a dose-dependent manner, and 100 ng·kg–1·min–1 of ANG II infusion doubled these levels (Table 1). There were no significant changes in TC, HDL-C, or non-HDL-C levels (calculated as TC – HDL-C; Table 1).

TGSR, hepatic lipid content, and lipogenesis. The TGSR determined by the Triton WR-1339 technique is shown in Fig. 1A. TGSR was twofold higher in rats with ANG II infusion (100 ng·kg–1·min–1) than in the saline infusion group. ANG II infusion (100 ng·kg–1·min–1) increased the hepatic TG content by 31% without affecting the TC content (Fig. 1B). As displayed in Fig. 1, TGSR and liver TG content were stimulated in a dose-dependent manner by chronic ANG II infusion. Different infusion rates of ANG II did not significantly alter the hepatic TC content. Lipogenesis was assessed by the incorporation of injected [2-3H]glycerol in TG in the liver. Both liver TG radioactivity and specific TG radioactivity were significantly increased by ANG II infusion (Fig. 2, A and B), suggesting an absolute increase of hepatic lipogenesis in the rats infused with ANG II.



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Fig. 1. Dose-dependent effects of ANG II infusion on triglyceride secretion rate (TGSR; A) and hepatic triglyceride (TG) content (B). ANG II was subcutaneously and continuously infused in the following 4 groups with different infusion rates: saline (n = 6); 10 ng·kg–1·min–1 (n = 8); 50 ng·kg–1·min–1 (n = 8); and 100 ng·kg–1·min–1 (n = 8) for 2 wk. TGSR was determined by the Triton WR-1339 technique. Total liver lipids were extracted according to the method of Bligh and Dyer (5). Data are expressed as means ± SD. One-way ANOVA revealed that TGSR and hepatic TG content are increased by ANG II infusion in a dose-dependent manner. TC, total cholesterol. NS, no significance. *P < 0.05 vs. rats with saline infusion. **P < 0.01 vs. rats with saline infusion. #P < 0.05 vs. 10 ng·kg–1·min–1 ANG II infusion group; {blacktriangleup}P < 0.05 vs. 50 ng·kg–1·min–1 ANG II infusion group.

 


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Fig. 2. [2-3H]glycerol incorporation in hepatic TG in rats infused with saline (n = 5) and ANG II (100 ng·kg–1·min–1) (n = 5) for 2 wk. [2-3H]glycerol was injected in femoral vein. The liver was removed 30 min after the injection, and total lipids were extracted according to the method of Bligh and Dyer (5). TG was separated on a TLC plate and counted by a liquid scintillation counter. Data are expressed as means ± SD. A: liver TG radioactivity; B: TG specific radioactivity. *P < 0.05 vs. rats with saline infusion.

 
FS-IVGTT in rats infused with ANG II (100 ng·kg–1·min–1) for 2 wk. Figure 3 depicts the profiles of plasma glucose and insulin in the FS-IVGTT, whereas the parameters obtained by Bergman's minimal model are shown in Table 2. The infusion of ANG II did not alter plasma glucose levels before or after the injection of glucose (Fig. 2A). However, ANG II treatment significantly increased both the basal insulin level and insulin responses after the intravenous glucose challenge (Fig. 2B). ANG II treatment doubled AUCI without affecting AUCG (Table 2). As a result, SI, indicating insulin-mediated glucose disposal, was markedly decreased by the ANG II infusion. Conversely, SG, indicating insulin-independent glucose disposal, was not significantly affected by ANG II infusion. Kg, indicating glucose disappearance rate, was also not significantly affected by the ANG II infusion.



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Fig. 3. Glucose (A) and insulin (B) levels during frequently sampled iv glucose tolerance test (FS-IVGTT) in rats with ANG II (100 ng·kg–1·min–1) or saline infusion for 2 wk. Data are expressed as means ± SD. {blacktriangleup}, Rats with ANG II infusion (n = 6); *, rats with saline infusion (n = 6).

 

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Table 2. Parameters calculated by Bergman's minimal model in frequently sampled intravenous glucose tolerance test

 
Time course of the effect of ANG II infusion on TGSR and other parameters. Infusion of ANG II (100 ng·min–1·kg–1) significantly elevated SBP and DBP within 1 day, and the values were elevated further after infusion for 1 wk (Table 3). Unlike BP, plasma levels of TG, NEFA, TC, and HDL-C were not significantly increased after 1 and 7 days of ANG II infusion compared with their own controls. Fasting plasma glucose and fasting plasma insulin levels were kept constant, and SI and SG were determined by the minimal model in FS-IVGTT. TGSR was comparable between the ANG II and saline infusion groups after 7 days of treatment (Table 3).


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Table 3. Blood pressure and parameters about lipid and glucose metabolism in rats at baseline 1 and 7 days after infusion of ANG II (100 ng·kg–1·min–1) or saline

 
Correlations between parameters related to BP, insulin sensitivity, and TG metabolism. Table 4 shows the correlations between various parameters in rats infused with ANG II (100 ng·min–1·kg–1) and saline for 14 days. Both SBP and DBP were significantly associated with the plasma insulin level, SI, TG, and TGSR. There were very strong correlations between the plasma TG and NEFA concentrations and TGSR, the hepatic TG content, or SI. There was also a substantial correlation between the hepatic TG content and TGSR, and either TGSR or hepatic TG content was positively correlated with the fasting plasma insulin level.


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Table 4. Correlations between various parameters in rats with ANG II (100 ng·kg–1·min–1) and saline infusion for 2 wk

 

    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We found that continuous infusion of ANG II for 14 days stimulates hepatic TG production in a dose-dependent manner and thereby increases the plasma TG concentration. The TG level was strongly correlated with TGSR (r = 0.88), suggesting that hypertriglyceridemia was mainly attributable to hepatic overproduction of TG. The stimulatory effect of ANG II on TGSR was further supported by significant increases of TG content and lipogenesis in the liver. There have been few studies examining the effect of ANG II on lipid metabolism. Patiag et al. (31) estimated TGSR by the Triton method in rats receiving an intravenous ANG II infusion. However, their treatment period was only 3 h, so they did not find any significant effects of ANG II on TGSR and plasma TG level. Diep et al. (11) measured plasma lipid levels in normal Sprague-Dawley rats after subcutaneous infusion of ANG II for 7 days at a dose of 120 ng·min–1·kg–1, but also did not find any changes of plasma lipids. These results suggest that ANG II may stimulate a step-up increase in TG production during a long-term period. Indeed, we found that TGSR did not increase significantly until infusion of ANG II had been continued for 14 days. There have been several reports on the changes of plasma lipid concentrations in gene-targeted hypercholesterolemic mice (such as apolipoprotein-E knockout mice or low-density lipoprotein receptor knockout mice) receiving chronic infusion of ANG II, which is an established animal model of aortic aneurysm (6, 10, 23). In those studies, long-term ANG II infusion at a high rate for a long period (i.e., 1,000 ng·min–1·kg–1 for 1 mo) did not affect plasma lipids (10). It seems likely that lipoprotein metabolism is inordinately altered in such hypercholesterolemic mice, which may make it difficult to detect relatively subtle changes of TG metabolism. The infusion rate of ANG II, 100 ng·min–1·kg–1, used for the rats in the current study is a common dosage employed by many other researchers (29, 25). In preliminary studies, we measured the plasma ANG II concentration by RIA in rats infused with ANG II (100 ng·min–1·kg–1) or saline and found that the ANG II level was only twofold higher in ANG II-infused rats than in saline-infused rats (220 ± 41 vs. 120 ± 37 pg/ml; data not shown). It has been reported that the plasma ANG II concentration in patients with renovasuclar hypertension is threefold higher than that in controls (17), suggesting that plasma ANG II levels in our ANG II-infused rats are within the physiological range. The renin-angiotensin system is locally stimulated in the majority of hypertensive subjects, even if their plasma ANG II level is not elevated (20, 21, 2). ANG II-infused rats seem to be a suitable animal model for investigating lipid metabolism in hypertension with increased ANG II action.

Several studies have shown that administration of ANG II impairs insulin sensitivity in vivo (33, 29), although the exact mechanisms are poorly understood. We also confirmed that chronic ANG II infusion caused selective impairment of insulin-mediated glucose disposal determined by Bergman's minimal model. It is speculated that ANG II constricts the vessels and decreases the blood flow, which may diminish glucose diffusion from the vessels and capillaries to insulin-dependent tissues (7), or ANG II may directly impair intracellular insulin signaling (12, 27). Ogihara et al. (29) demonstrated that chronic ANG II infusion impaired insulin-induced glucose transporter (GLUT)-4 translocation in the skeletal muscle of rats. Conversely, Henriksen et al. (15) demonstrated that irbesartan, an ARB, stimulates glucose transport in skeletal muscle with increased GLUT-4 protein expression in insulin-resistant Zucker fatty rats. Thus GLUT-4 may be a major molecular target for ANG II in bringing about an impairment of insulin-induced glucose disposal within the whole body. A number of clinical and experimental investigations have demonstrated that hepatic TG production can be stimulated by insulin resistance (8, 26). Thus it is reasonable to assume that the increase of TG production during ANG II infusion was the result of the simultaneous onset of insulin resistance. The NEFA level was also significantly increased by ANG II infusion, probably because insulin resistance developed in adipose tissue, and this may have contributed to TG overproduction in the liver. It is technically difficult to measure TGSR and SI in the same animal. However, SI could be estimated from the fasting plasma insulin level in normal rats. TGSR and the hepatic TG content were both strongly associated with the plasma insulin level, suggesting that insulin resistance caused by ANG II infusion played an important role in stimulating hepatic TG production. Besides ANG II-infused hypertensive rats, we observed a similar relationship between TG overproduction and insulin resistance in obese rats (37, 32) or fructose-fed rats (30). On the other hand, different doses of ANG II infusion led to increases of the same extent in insulin, so the dose dependently increased TGSR may not be completely decided by insulin sensitivity. It is also possible that ANG II stimulated hepatic TG production through unknown mechanisms other than insulin resistance.

There have been several clinical investigations into the effect of ARB therapy on plasma TG levels, but most have failed to find significant lipid-lowering activity (38, 1). We recently reported that a new ARB, olmesartan medoxomil, improved TG overproduction and insulin resistance in fructose-fed rats and Zucker fatty rats but did not affect the TGSR or insulin sensitivity in their respective controls, i.e., normal chow-fed rats and Zucker lean rats (30, 32). Our previous study suggests that a lipid-lowering action of ARB therapy is not always observed, but only becomes manifest in the insulin-resistant state. The results of our ANG II infusion study do not completely contradict the findings of the ARB study. There are at least two identified types of receptor through which ANG II can signal (22). ARBs are selective blockers for ANG II type 1 receptor, whereas exogenous ANG II stimulates both type 1 and 2 receptors. If the type 2 receptor plays an important role in TG metabolism, it becomes difficult to estimate the influence of ANG II on TG metabolism from the effect of ARBs. Darimont et al. (9) identified that type 2 receptor is essential for the regulation of differentiation of preadipose cells. Jones et al. (18) and Kim et al. (24) reported that ANG II increases lipogenesis in both 3T3-L1 adipocytes and human adipocytes. Surprisingly, this effect was completely blocked by coincubation with an antagonist of ANG II type 2 receptors. Therefore, there is a possibility that the stimulatory effect of ANG II on TG production is mediated via the type 2 receptor in adipose tissue. According to Jones et al. (18), ANG II-induced hepatic overproduction of TG might be primarily attributable to increased fatty acid flux in the liver secondary to enhanced lipogenesis in adipose tissue. Further studies will be required to explore whether ANG II can directly stimulate TG production independent of its effect on insulin resistance.

In conclusion, chronic infusion of ANG II increased hepatic TG production partly in association with the simultaneous development of insulin resistance. Our results may suggest a new mechanism for the intimate association between hypertension and dyslipidemia.


    ACKNOWLEDGMENTS
 
We thank Dr. Kenta Okada for help in lipogenesis assay and Hiroko Takeuchi for excellent technical assistance.


    FOOTNOTES
 

Address for reprint requests and other correspondence: T. Hirano, First Dept. of Internal Medicine, Showa Univ. School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-666, Japan (E-mail: hirano{at}med.showa-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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