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Article

Dietary Fat Alters HIV Protease Inhibitor–Induced Metabolic Changes in Mice

Department of Metabolic Diseases, Glaxo Wellcome Incorporated, Research Triangle Park, NC 27709

¹To whom correspondence and reprint requests should be addressed.

	ABSTRACT

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Human immunodeficiency virus (HIV) protease inhibitors (PI) may alter lipid metabolism in patients with acquired immunodeficiency syndrome (AIDS). However, the influence of dietary fat on the metabolic effects of PI therapy remains unknown. AKR/J mice were fed high or low fat diets and treated with the PI indinavir (IDV), nelfinavir (NFV), saquinavir (SQV) or amprenavir (APV) by subcutaneous delivery for 2 wk. Serum concentrations of glucose, insulin, triglyceride, free fatty acid, glycerol, pancreatic lipase, bilirubin, alkaline phosphatase, blood urea nitrogen and PI, and interscapular and epididymal fat weights were determined. Some metabolic effects of PI were dependent on diet. IDV- and NFV-treated mice had greater serum glucose concentration and body weight; IDV-treated mice had lower serum insulin; NFV-treated mice had greater interscapular fat mass; and SQV treated mice had lower serum triglyceride concentration than control mice fed the low but not the high fat diet. In contrast, NFV- and IDV-treated mice had greater triglyceride concentration and blood urea nitrogen, and SQV treated mice had greater serum cholesterol than control mice fed the high but not the low fat diet. The serum concentration of SQV was lower in mice fed the high fat compared with the low fat diet. Other effects were not dependent on diet. IDV- and NFV-treated mice had greater fatty acids, and IDV-treated mice had greater pancreatic lipase, bilirubin and alkaline phosphatase than control mice fed either diet. APV treatment had little effect on these serum measurements. Thus, changes in dietary fat can influence some but not all of the effects of PI on metabolism. Furthermore, each PI produces different effects in vivo, indicating that various PI affect distinct metabolic pathways.

KEY WORDS: • dyslipidemia • fat • HIV • protease inhibitors • lipodystrophy

	INTRODUCTION

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The human immunodeficiency virus (HIV)² -1 aspartyl protease provides essential proteolytic processing of viral proteins during the maturation of virions in HIV-1–infected cells (Debouck 1992 ). Inhibition of this enzyme with protease inhibitors (PI) results in significant antiviral activity and increases the survival rate of patients with acquired immunodeficiency syndrome (AIDS) (Mocroft et al. 1998 , Sherer 1998 ). However, PI therapy is sometimes associated with adverse events, which may include fat redistribution, insulin resistance, diabetes and hyperlipidemia (Behrens et al. 1998 , Carr et al. 1998a and 1998b , Danner et al. 1995 , Massip et al. 1997 , Miller et al. 1998 , Sullivan and Nelson 1997 , Viraben and Aquilina 1998 , Walli et al. 1998 ). Although changes in fat metabolism are observed with PI therapy, altered fat metabolism is also found in HIV-infected individuals in the absence of therapy or treated with non-PI–containing regimens (e.g., reverse transcriptase inhibitors) (Grunfeld et al. 1991 , Hadigan et al. 1999 , Lo et al. 1998 , Madge et al. 1999 ). Moreover, the use of a nucleoside analog, stavudine, is significantly associated with decreased subcutaneous fat and increased serum levels of glucose, insulin and triglycerides (Saint-Marc et al. 1999 ). Thus, there may be multiple causes of the metabolic abnormalities reported in HIV-infected individuals. Because HIV patients are treated with a combination of drugs, the contribution of PI to alterations in fat metabolism is unclear.

Susceptibility to metabolic disorders, such as obesity and diabetes, results from multiple genetic and environmental components. For example, genetic analysis reveals that genes on chromosomes 2 and 15 influence susceptibility to diabetes in Mexican Americans (Cox et al. 1999 ). Moreover, pre- and postnatal exposures as well as diet and physical activity in adulthood markedly affect risk of developing diabetes and obesity in the Pima Indians (Pratley 1998 ). The observation that not all patients treated with PI develop fat redistribution, dorsocervical fat pads (buffalo humps), dyslipidemia or diabetes (Carr et al. 1998a , Lo et al. 1998 , Walli et al. 1998 ) supports the hypothesis that susceptibility to metabolic diseases varies with environment, duration of therapy and/or genetics.

Studies involving inbred strains of mice show that the AKR/J strain is susceptible to obesity and other metabolic changes when fed a high fat diet, but not when fed a high carbohydrate diet (West et al. 1992 ). Although PI therapy and diet may influence changes in fat distribution and metabolism, the interaction between PI and diet is unknown. This study describes the effects of various PI on metabolism in AKR/J mice fed high and low fat diets.

	MATERIALS AND METHODS

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Materials.

This research complied with the NIH guidelines on laboratory animal care (NRC 1985 ) and Glaxo Wellcome company policy on the care and use of mice and related codes of practice. The protease inhibitors amprenavir (APV), indinavir (IDV), nelfinavir (NFV) and saquinavir (SQV) used in these studies were obtained from the Medicinal Chemistry Department at Glaxo Wellcome (Research Triangle Park, NC). These compounds were determined to be >95% pure by HPLC and/or nuclear magnetic resonance analysis.

Experimental animal protocol.

Age- and weight-matched male AKR/J mice (Jackson Laboratories, Bar Harbor, ME) were housed 5 mice/cage at 21°C and 50% relative humidity with a 12-h light:dark cycle. Starting at 4 wk of age, the mice were fed a low fat diet (12% energy as fat, 16% as protein and 72% as carbohydrate) or a high fat diet (58% energy as fat, 16% as protein, and 26% as carbohydrate; D12331, Research Diets, New Brunswick, NJ). The compositions of these diets are reported elsewhere (Surwit et al. 1995 ). In sum, in mice fed a high fat diet, the source of fat was 93% hydrogenated coconut oil and 7% soybean oil, protein was 100% casein, and carbohydrate was 49% maltodextran and 51% sucrose. In mice fed a low fat diet, the source of fat was 62% hydrogenated coconut oil and 38% soybean oil, protein was 100% casein, and carbohydrate was 17% maltodextran and 83% sucrose. Mice were fed the diet from 4 to 10 wk of age and treated with the PI from 8 to 10 wk of age.

Three-week, continuous-release pellets containing 20 mg of PI, with an approximate release rate of 27–32 mg/(kg · d), were prepared by Innovative Research of America (Sarasota, FL). This dose represents clinically relevant concentrations for PI [30–60 mg/(kg · d)]. A trochar was used to implant three pellets subcutaneously in the back of each mouse (8 mice/group) starting at 8 wk of age according to the manufacturer’s specifications (Innovative Research of America). There were no visual signs of swelling or inflammation at the site of pellet implant after physical examination at necropsy. This method of drug delivery was chosen to accelerate the onset of PI-associated adverse events, to minimize animal discomfort that is accompanied by multiple oral doses (e.g., 3 times per day), and to eliminate differences in oral availability of the drugs and their interaction with food. After 2 wk, the mice were anesthetized with isoflurane, blood drawn by cardiac puncture, and measurements of glucose, total cholesterol, triglycerides, nonesterified free fatty acids (NEFA), glycerol, alkaline phosphatase (ALP), bilirubin, blood urea nitrogen (BUN), pancreatic lipase, ß-hydroxybutyric acid, insulin, C-peptide and leptin were obtained using an automated chemistry analyzer (Technicon Axon, Tarrytown, NY). On the basis of background studies of the effects of multiple pharmacologic agents on metabolism in mice (Lenhard et al. 1999 ), we found 2 wk to be a sufficient time to allow for significant changes in the blood chemistry tests reported in this study. On the day of necropsy, blood was withdrawn 4–5 h (1000–1100 h) after initiation of the light cycle. Food was not withdrawn from the cages before necropsy, although food consumption decreases during the light cycle. All blood chemistry tests, with the exception of insulin, C-peptide and leptin, were conducted as previously described (Lenhard et al. 1999 ). Linco Research (St. Charles, MO) measured serum insulin, C-peptide and leptin concentrations. Organ weights were determined at the end of the study and body weights were recorded at the beginning and end of the study. Serum concentrations of the PI were determined by a mass spectrometer in the liquid chromatography (LC)/mass spectrometry (MS)/MS mode.

The data were calculated as the mean and SEM from experiments performed on eight mice per treatment group. Statistical analysis was performed with JMP (SAS Institute Inc., Cary, NC) version 3.2.6 using Dunnett’s test. P-values < 0.05 were considered to be significant. Correlation coefficients were determined by regression analysis using Microsoft Excel (Seattle, WA). Ritonavir was not included in this study in part because its effects in rodents are described elsewhere (Ye et al. 1998 ).

	RESULTS

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Fat depot and body weights.

Mice fed a high fat diet gained 220% more weight than mice fed a low fat diet (Table 1 ). IDV and NFV treatment had no effect on weight gain in mice fed a high fat diet but increased weight gain in mice fed a low fat diet. In contrast, APV treatment decreased weight gain in obese mice fed a high fat but not a low fat diet. SQV did not affect body weight. Although IDV, NFV and APV altered weight gain, these changes were within the normal range for placebo-treated (control) mice (i.e., APV-treated mice fed a high fat diet gained a similar amount of weight as control mice fed a low fat diet, P = 0.17).

Insulin and glucose response in PI-treated mice.

As expected, serum glucose and insulin concentrations and the insulin resistance index were greater (P < 0.05) in mice fed a high fat diet (Table 2 ). PI treatment influenced serum glucose and insulin levels and the insulin resistance index differently in mice fed the high and low fat diets. Although PI treatment had no significant effect on serum glucose and insulin concentrations in mice fed a high fat diet, IDV- and NFV-treated mice had a greater serum glucose concentration than control mice fed a low fat diet. Moreover, IDV-treated mice had lower serum insulin levels and insulin resistance than control mice fed a low fat diet. APV and SQV treatment did not significantly affect serum glucose or insulin concentrations relative to the control group (P > 0.05, Table 2 ). Regression analysis revealed no significant correlation between the mice fed low and high fat diets with respect to the effects of PI on serum glucose, insulin and the insulin resistance index (P > 0.2). C-peptide and leptin levels were unaffected in all treatment groups (data not shown).

AKR/J mice fed a high fat diet had greater serum concentrations of NEFA (P = 0.05), glycerol (P = 0.008), cholesterol (P < 0.001) and pancreatic lipase (P = 0.009), but not serum triglycerides (P = 0.18) than mice fed a low fat diet (Table 3 ). Compared with control mice fed either diet, NEFA were greater in IDV- and NFV-treated mice, glycerol was greater in NFV-treated mice and pancreatic lipase was greater IDV-treated mice (Table 3) . Comparing mice fed a high fat diet with those fed a low fat diet, the correlation coefficient for NEFA was 0.92 (P = 0.02), indicating that PI treatment has the same effect on NEFA in mice fed both diets. However, the effect of PI on serum triglyceride levels was different in mice fed high and low fat diets (Table 3) . In mice fed a high fat diet, serum triglyceride levels were greater in IDV- or NFV-treated mice compared with control mice, whereas APV or SQV treatment had no significant effect on serum triglycerides. In contrast, in mice fed a low fat diet, the serum triglyceride level was lower in SQV-treated mice compared with control mice. Moreover, cholesterol levels were greater in SQV-treated mice relative to control mice fed a high fat but not a low fat diet (Table 3) . When mice fed high and low fat diets were compared, the correlation coefficient for triglycerides (r = 0.1, P = 0.8) and cholesterol (r = 0.6, P = 0.3) were not significant. Finally, PI treatment of mice fed either diet had little effect on serum concentrations of ß-hydroxybutyric acid (data not shown).

The influence of diet on the relative safety of PI was also determined. Biochemical tests were performed to detect abnormal function of liver [alanine aminotransferase (ALT), ALP and bilirubin], heart/muscle [lactate dehydrogenase (LDH)], and kidney (BUN) (Table 4 ). Because this was a preliminary screen, specific isozymes of ALP and LDH were not analyzed. NFV, APV or SQV treatment had no significant effect on ALP, bilirubin, ALT or LDH. In mice fed low or high fat diets, ALP was greater in those treated with IDV than in control-treated mice. Similarly, IDV-treated mice fed high fat had greater serum levels of bilirubin. Relative to control mice fed a high fat diet, IDV- or NFV- but not APV- or SQV-treated mice had greater BUN concentrations. Because mice fed the low and high fat diets were fed equivalent amounts of protein (16% of energy) and the treated groups were compared with their respective controls, the differences in BUN probably reflect specific effects due to each drug and not changes in dietary protein. BUN was correlated negatively with ALP in the PI-treated mice fed a low fat diet (r = -0.88, P = 0.05) and correlated positively with ALP in the PI-treated mice fed a high fat diet (r = 0.87, P = 0.05). Thus, diet may influence the effects of PI on BUN concentration but not ALP activity in these mice.

Diet had no significant effect on the serum concentrations of APV, IDV or NFV (Table 5 ). In contrast, the serum concentration of SQV was 150% greater in mice fed a low fat diet than in mice fed a high fat diet. Mice fed either a high or low fat diet had lower serum concentrations of NFV and IDV than APV or SQV (Table 5) . In contrast, NFV and IDV treatment increased serum lipids more than APV or SQV (Table 3) . Thus, mice treated with NFV and IDV had lower serum drug levels but greater serum lipid levels than mice exposed to APV or SQV.

	DISCUSSION

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The mechanism whereby PI alters fat metabolism is unclear. Because serum NEFA levels were greater in IDV- and NFV-treated mice fed a low fat diet, it is possible that lipolysis was increased in these mice. This is consistent with the observation that insulin inhibits lipolysis, and insulin levels were lower in these mice. However, because NEFA and glycerol levels were greater and insulin levels were unaffected in IDV- and NFV-treated mice fed a high fat diet, it is also possible that these PI alter lipolysis through a mechanism independent of insulin. Alternatively, increased triglyceride production may contribute to the hyperlipidemia observed in IDV- and NFV-treated mice fed a high fat diet. Consistent with this hypothesis, NFV and RTV treatment increased serum triglyceride levels by 140 and 260%, respectively, after 16 h food deprivation in AKR/J mice treated with Triton WR1339, an inhibitor of triglyceride hydrolysis (Lenhard and Croom, unpublished observation). Another possibility is that increased pancreatic lipase activity, an enzyme that hydrolyzes diglycerides in the gut, contributes by increasing dietary fat absorption. Further information is required to discriminate among these possibilities.

The PI are unique agents with varying pharmacologic properties. For example, IDV is the only PI to significantly increase retinoic acid–inducible ALP in cultured cells (Lenhard et al. 2000 ) and serum ALP or lipase activity in AKR/J mice. Moreover, the experiments described in this report demonstrate that the serum concentration of SQV, but not other PI, was lower in mice fed a high fat diet than in those fed a low fat diet. Thus, diet may influence the pharmacokinetic properties of SQV more than other PI. Additionally, differences in relative potency may contribute to the pharmacologic differences among PI. For example, the serum concentrations of APV and SQV were greater than those of IDV and NFV in mice fed a high fat diet. However, IDV and NFV increased serum triglycerides and fatty acids more than APV and SQV in mice fed a high fat diet. Thus, these mice were more susceptible to dyslipidemia when treated with IDV or NFV than with APV or SQV. The observation that the APV-treated mice fed a high fat diet gained less weight than obese control mice might explain why they had fewer changes in serum lipid levels. Taken together, these data are consistent with the suggestion that each PI should be considered as a distinct agent with unique pharmacologic properties (Lenhard et al. 2000 ).

Although AIDS therapy is associated with increased abdominal and dorsocervical fat (Lo et al. 1998 , Miller et al. 1998 ) and decreased subcutaneous fat (Carr et al. 1998a , Massip et al. 1997 , Viraben and Aquilina 1998 ), little is known about the factors that influence the susceptibility of patients to PI-associated fat redistribution. The observation that NFV or IDV treatment affected fat mass only in mice fed a low fat diet raises the possibility that susceptibility to PI-induced fat redistribution may be determined in part by diet. This is consistent with the observation that IDV and NFV treatment increased weight gain only in mice fed a low fat diet. Because AKR/J mice are prone to diet-induced obesity, it is also possible that genetic factors influenced the ability of these PI to affect fat deposition and weight gain. Consistent with this hypothesis, we recently found that obesity-resistant SWR/J mice treated with PI were less likely to develop metabolic changes than AKR/J mice (Weiel et al. 1999 ). Because diet and genetics influence human obesity (Pratley 1998 ) and diet influences some of effects of PI in obese AKR/J mice, it seems likely that genetic factors will also alter susceptibility to the effects of PI on fat metabolism in humans. Future studies comparing the effects of PI in obesity-resistant and obesity-prone mice should provide useful insight into the interactions of genetics and diet on PI-induced fat redistribution. These studies should include monitoring changes in subcutaneous and total body fat over longer periods of time, both as monotherapies and in combination with other agents, such as reverse transcriptase inhibitors.

Although PI treatment may cause some similar effects in HIV patients and AKR/J mice, the in vivo mouse studies do not appear to mimic the peripheral lipodystrophy syndrome seen in patients treated with these drugs. There are several differences between clinical studies and the mouse study reported here. For example, PI treatment decreased insulin levels in mice but the opposite may occur in humans (Carr et al. 1998a , Walli et al. 1998 ). Moreover, interscapular (brown) fat and epididymal (testicular) depots are more abundant in rodents than humans. Furthermore, in HIV patients, these drugs are administered orally, which results in peak and valley effects on drug levels in the serum (Balani et al. 1996 , Danner et al. 1995 , Pai and Nahata 1999 ). In AKR/J mice, the drugs (60 mg/mouse) were administered by continuous subcutaneous delivery, thus minimizing the effects of food on intestinal adsorption of the drugs and fluctuations in serum drug levels produced by multiple oral doses. In HIV patients, the maximum serum concentrations for protease inhibitors are >1 µmol/L (Balani et al. 1996 , Danner et al. 1995 , Montvale et al. 1999, Pai and Nahata 1999 ). In AKR/J mice, the maximum concentration for the protease inhibitors was 110 nmol/L, indicating that the effects of the PI in these mice occurred at lower peak serum concentrations than that found in humans. Also, unlike many clinical studies, the mice were treated for a relatively short period of time (2 wk). Thus, it is possible that different effects, such as increased insulin resistance or altered adiposity, may be observed over a longer treatment period. Additionally, many confounding factors may affect PI toxicity in the clinic, including differences in genetics, pharmacokinetics, disease progression (viral load or T-cell count) or drug interactions, such as the use of reverse transcriptase inhibitors or retinoids (Danner et al., 1995 , Grunfeld et al. 1991 , Lenhard et al. 2000 , Saint-Marc et al. 1999 , Weiel et al. 1999 ). Indeed, the dyslipidemia that is observed in HIV-infected individuals in the absence of therapy (Grunfeld et al. 1991 ) and the fat redistribution in patients treated with non-PI–containing regimens including stavudine (Saint-Marc et al. 1999 ) indicate that factors other than PI contribute to the metabolic abnormalities reported in the clinic.

Because studies analogous to those described in this report have not been carried out in humans, caution should be used when extrapolating the results from rodents to humans. Nonetheless, the data presented here indicate that PI treatment has different effects in mice fed high and low fat diets, suggesting that dietary modifications could alter some adverse reactions to PI in humans. Clinical studies that account for changes in dietary fat are required to identify ways of decreasing the side effects associated with AIDS therapies.

	ACKNOWLEDGMENTS

 
The authors thank Jane Binz and Patricia Wheelan for assistance with the clinical chemistry measurements and Mike Lutz for help with statistical analysis.

	FOOTNOTES

 
² Abbreviations used: AIDS, acquired immunodeficiency syndrome; ALP, alkaline phosphatase; ALT, alanine aminotransferase; APV, amprenavir; AST, aspartate aminotransferase; BUN, blood urea nitrogen; HIV, human immunodeficiency virus; IDV, indinavir; LDH, lactate dehydrogenase; NEFA, nonesterified fatty acid; NFV, nelfinavir; PI, protease inhibitor; SQV, saquinavir.

Manuscript received December 28, 1999. Initial review completed February 14, 2000. Revision accepted May 22, 2000.

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