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Journal of the American College of Nutrition, Vol. 18, No. 1, 36-42 (1999)
Published by the American College of Nutrition

Alterations in Carbohydrate and Lipid Metabolism Induced by a Diet Rich in Coconut Oil and Cholesterol in a Rat Model

Ma Angeles Zulet, PhD, Ana Barber, PhD, Henri Garcin, PhD, Paul Higueret, PhD and José Alfredo Martínez, PhD, FACN

Department of Physiology and Nutrition (M.A.Z., A.B., J.A.M.), University of Navarra, Pamplona, SPAIN
Department of Nutrition-ISTAB (H.G., P.H.), University of Bordeaux, Talence, FRANCE

Address reprint requests to: J. Alfredo Martinez, PhD, Department of Physiology and Nutrition, University of Navarra, Irunlarrea s/n, 31008, Pamplona, SPAIN


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective: The type of dietary fat as well as the amount of cholesterol occurring in the diet have been associated with several metabolic disorders. Thus, the aim of the present study was to investigate the influence of a hypercholesterolemic diet enriched with coconut oil and cholesterol on carbohydrate and lipid metabolism in a rat model.

Methods: Twenty male Wistar rats weighing about 190 g were assigned to two dietary groups. One group received a semipurified control diet and the other was given a diet enriched in coconut oil (25% by weight) and cholesterol (1% by weight) for 26 days.

Results: Our results indicated a significant increase in serum total cholesterol (+285%; p<0.001), low-density lipoproteins (+154%; p<0.01), liver cholesterol (+1509%; p<0.001), as well as a significant increase in liver weight (+46%; p<0.001) in those rats fed the hypercholesterolemia-inducing diet as compared to controls. Moreover, a significant decrease in serum high-density lipoproteins (-67%; p<0.001), triacylglycerols levels (-33%; p<0.05), and abdominal fat weight (-39%; p<0.01) were found. The observed alterations in serum lipid and lipoprotein profile resembled a situation of type IIa hyperlipidemia in humans. Measurement of several enzymes concerned with lipid utilization revealed a significant increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity (+68%; p<0.01) in the liver of animals fed the hypercholesterolemic diet, while a significant reduction in plasma lecithin-cholesterol acyltransferase activity (-66%; p<0.001) was found. The situation of hypoglycemia (-18%; p<0.05) was accompanied by lower levels of serum insulin (-45%; p<0.01) and liver glycogen (-30%; p<0.05) in the hypercholesterolemic rats. Furthermore, glucose utilization was altered since lower glucose-6-Pase (-33%; p<0.05) and increased glucokinase (+212%; p<0.001) activities in the liver were found in the rat model of hypercholesterolemia.

Conclusion: These results provide new evidence that a diet-induced hypercholesterolemia in rats is associated with several adaptative changes in carbohydrate metabolism. These findings may be of importance not only considering the role of western diets on cholesterogenesis, but also in other metabolic disturbances involving lipid and carbohydrate metabolism.

Key words: carbohydrate metabolism, lipid metabolism, coconut oil, cholesterol, hypercholesterolemia, animal model


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dietary intake influences nutrient and turnover [1]. Thus, different studies have shown that the type and amount of carbohydrate feeding is associated with changes in the levels, composition and metabolism of serum lipoproteins [2], triglycerides [3], and other lipids [4]. Furthermore, dietary trials in humans and experimental animals have revealed that the concentration of serum cholesterol is affected by the protein content [5] and source [6]. Finally, lipid structure, composition and configuration in addition to excessive fat and cholesterol consumption affect the lipid profile in plasma [7], as well as fat tissue deposition [8] and gene expression of lipoproteins and their receptors [9]. In this context, the intake of diets containing a high proportion of saturated fatty acids, mainly myristic, lauric and palmitic acids has been associated with hypercholesterolemia [10].

Experimental and epidemiological studies demonstrate that elevated levels of LDL-cholesterol and apolipoprotein B constitute a major risk factor for coronary heart disease (CHD) [11]. These alterations appear to be due to impaired catabolism rather than increased synthesis [12]. However, the precise mechanisms by which fatty acids influence blood lipid levels are not fully understood [13].

In addition to effects on lipid profile, dietary fats may induce other physiological responses. In this sense, investigations concerning the glucose-fatty acid interactions in health and disease are being initiated [14].

Therefore, the aim of this study was to evaluate the influence of a hypercholesterolemic diet on lipid profile, metabolism and selected enzyme activities (lipoprotein lipase, lecithin:cholesterol acyltransferase, 3-hydroxy-3-methylglutaryl-CoA reductase) in a rat model. Also, the current investigation assessed the influence of a hypercholesterolemic diet on several indicators of glucose turnover by measuring plasma glucose concentrations and two enzymes involved in glyconeogenesis (glucose-6-phosphatase) and glucose utilization (glucokinase).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Diets
Male Wistar rats weighing about 190 g were obtained from the Center of Applied Pharmacology (CIFA), Spain. Animals were housed in groups of four animals in a controlled environment (22–24° and 12-hour light/dark cycle from 8:00 a.m. to 8:00 p.m.) with food and water freely available. The period of feeding (26 days) was carried out with different dietary formulations (Table 1). Thus, 10 rats received a control diet (C), while the other group (n=10) was fed a hypercholesterolemic (H) diet enriched in coconut oil (25% by weight) and cholesterol (1% by weight).


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  		Table 1. Composition of the Diets (g/kg)

 
Experimental Procedure
At the end of the experimental period, the rats were fasted for 16 hours and then sacrificed by decapitation between 9:00 and 11:00 a.m. Serum was separated from blood samples and total cholesterol (CHOL), high-density lipoproteins (HDL-cholesterol), low-density lipoproteins (LDL-cholesterol), glucose (Glc) and triacylglycerols (TG) were measured by using appropriate kits supplied by Boehringer Mannheim (Boehringer Mannheim, France S.A.). For the quantitative determination of non-esterified fatty acids (NEFA) in serum an enzymatic colorimetric kit of Wako (Wako Chemicals Gmbh, Germany) was utilized. Serum insulin was determined using a radioimmunoassay kit of Biomedica (Sorin Biomedica, France S.A.).

The liver and aorta from all rats were removed, weighed and frozen at -20°C. Liver glycogen was analyzed by the method described by McGarry and Kawajima [15]. Aorta cholesterol was extracted with hexane and spectrophotometrically determined by using the o-phthaldialdehyde reagent as previously described by Rudel and Morris [16]. Liver cholesterol was analyzed after extraction with hexane [17] and measured by using the method described for aorta cholesterol [16].

Lipoprotein lipase (LPL) activity was determined in adipose tissue by a fluorometric assay according to Del Prado et al [18]. Dibutyrilfluoresceine was used as substrate for the enzyme and the fluoresceine liberated by enzymatic hydrolysis was measured. The activity is expressed as nmoles of fluoresceine released per minute per mg of protein. The protein concentration was measured by the method of Bradford [19].

Lecithin:cholesterol acyltransferase (LCAT) activity in plasma was determined by measuring the conversion of radiolabeled cholesterol to cholesteryl ester after incubation of plasma with a substrate including labeled cholesterol and apo A-I prepared by the cholate dialysis procedure [20]. The activity is expressed as nmoles of cholesterol esterified per minute per mg of protein.

The enzyme 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase was isolated from hepatic microsomes and assayed spectrophotometrically at 340 nm by measuring the rate of nicotinamide adenine dinucleotide phosphate (NADP) release [21]. The activity is expressed as nmoles of NADP per minute per mg of protein.

Glucose-6-phosphatase (Glc-6-Pase) enzyme was isolated from hepatic microsomes according to Mithieux et al [22]. The resulting microsomal pellet was resuspended in a buffer containing glucose-6-phosphate. The activity of this enzyme was determined by measuring phosphorus production [23].

Glucokinase (GK) assay was carried out in liver according to Newgard et al [24]. The release of NADH by an exogenous enzyme, glucose-6-phosphate dehydrogenase, with glucose-6-phosphate as substrate, was measured spectrophotometrically at 340 nm.

Statistical Analysis
The results are expressed as the mean±SEM and they were statistically evaluated by the Student’s t test or by the Mann-Whitney test as appropriate. Differences were considered statistically significant if the p value was <0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
No significant changes in body weight rates were observed, although fat stores in the abdominal region were depleted (-39%; p<0.01) and liver weight was markedly increased (+46%; p<0.001) in those animals fed the hypercholesterolemia inducing diet as compared to control rats (Table 2).


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  		Table 2. Liver, Abdominal Fat and Final Body Weights, Total Cholesterol in Liver and Aorta of Rats Fed Control (C) and Hypercholesterolemic (H) Diets for 26 Days

 
Feeding animals with a high-fat diet enriched with coconut oil and cholesterol produced a significant elevation in serum CHOL concentrations (+285%; p<0.001), which was accompanied by a decrease in HDL-cholesterol (-67%; p<0.001) and TG concentrations (-33%; p<0.05) in serum, as well as an increase in LDL-cholesterol (+154%; p<0.01). Serum NEFA levels were similar in both dietary treatments. Moreover, these alterations in serum lipid profile (Table 3) were linked with an increase in liver (+1509%; p<0.001) and aorta (+24%; p<0.057) cholesterol deposition (Table 2).


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  		Table 3. Total Cholesterol (CHOL), High-Density Lipoprotein (HDL), Low-Density Lipoprotein (LDL), Triglycerides (TG) and Fatty Acid (FA) Concentrations in Serum, Lecithin:Cholesterol Acyltransferase (LCAT) Activity in Plasma, Hydroxy-3-Methylglutaril-CoA Reductase (HMGCoA) Activity in Liver and Lipoprotein Lipase (LPL) Activity in Adipose Tissue of Rats Fed Control (C) and Hypercholesterolemic (H) Diets for 26 days

 
The measurement of several enzymes concerned with lipid utilization revealed that HMGCoA reductase activity in liver was significantly increased (+68%; p<0.01), while LCAT activity in plasma was markedly reduced (-66%; p<0.001), although no changes were found in LPL activity in the adipose tissue of those animals fed the hypercholesterolemic diet as compared to controls (Table 3).

The hypoglycemia (-18%; p<0.05) found in animals fed the high-fat diet was accompanied by statistically lower levels in serum insulin (-45%; p<0.01) and liver glycogen (-30%; p<0.05). Moreover, the hypercholesterolemic animals showed statistical differences in glucose utilization as measured by means of Glc-6-Pase (-33%; p<0.05) and GK (+212%; p<0.001) activities in the liver (Table 4).


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  		Table 4. Glucose (Glc) and Insulin Concentrations in Serum, Glycogen in Liver, Glucokinase (GK) and Glucose-6-Phosfatase (Glc-6-Pase) Activities in Liver of Rats Fed Control (C) and Hypercholesterolemic (H) Diets for 26 Days

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It has been well established that nutrition plays an important role in the etiology of hyperlipidemias and atherosclerosis. Several animal and human studies have confirmed the hypercholesterolemic properties of saturated fatty acids and cholesterol which include increasing total cholesterol and altering lipoprotein pattern [25,26] and whose mechanisms remain under study [27,28]. Moreover, other potential physiological interactions concerning the carbohydrate metabolism cannot be ruled out [14].

Cholesterol feeding has been often used to elevate serum or tissue cholesterol levels to assess hypercholesterolemia-related metabolic disturbances in different animal models [29,30]. However, it is assumed that a high level of saturated fat in addition to cholesterol is required in the rat model [31]. In this study, hypercholesterolemia was induced in rats by adding cholesterol (1%), cholic acid (0.5%) and coconut oil (25%) to the diet for 26 days. This diet has been employed by different authors in previous investigations [32–35].

Rat body weights were similar in control and hypercholesterolemic groups, while a marked decrease in abdominal fat was found in those rats fed the cholesterol and fat saturated enriched diet. This nutrient partitioning (maintenance of body weight and reduction in fat) has been attributed to ketogenic mechanisms and a reduction in food intake [32]. However, other reports have found increases in body fat and weight after the intake of high-fat diet [36].

Furthermore, liver weights were significantly enhanced by the intake of a hypercholesterolemic diet as compared to control rats, and it was accompanied by an increase in the liver and aorta cholesterol content.

Determinations of the lipid profile in serum from rats fed a diet rich in sucrose, coconut oil and cholesterol and containing casein as the protein source revealed higher levels of serum CHOL as compared to controls. The situation of hypercholesterolemia was accompanied by a decrease in TG and HDL-cholesterol and an increase in LDL-cholesterol levels in serum, which resembles a situation of type IIa hyperlipidemia in humans [37].

These results are in agreement with previous studies carried out in animals and humans fed different amounts and types of fat, in which the hypercholesterolemic effect was attributed to some saturated fatty acids, mainly myristic, lauric and palmitic acids, occurring in the coconut oil [38–40]. Furthermore, dietary fat saturation and cholesterol have been shown to affect postprandial lipoprotein response [41], apolipoprotein gene expression [42], in addition to changes in plasma cholesterol concentrations [43].

On the other hand, the assessment of HMGCoA reductase, the rate-determining enzyme in cholesterol biosynthesis, revealed a higher activity in the liver of animals fed saturated fatty acids. This increased enzyme activity may be attributed to a higher availability of acetyl CoA, which stimulated the cholesterogenesis rate [44]. Moreover, this result could be associated with a down-regulation in LDL receptors by the cholesterol and saturated fatty acids included in the diet, which could also explain the elevation in serum LDL-cholesterol levels [45,46].

Also, it has been reported that LCAT activity, the enzyme involved in the transesterification of cholesterol, the maturation of HDL and the flux of cholesterol from cell membranes into HDL [27], tends to decrease in familial or diet-induced situations of hypercholesterolemia [47,48] as occurred in this experimental trial. Moreover, previous reports carried out with a similar hypercholesterolemic dietary pattern has suggested the occurrence of an abnormal apoprotein (apo A-I) in HDL [35,49], which could also explain some changes in the LCAT activity.

No significant changes were found in LPL activity, the enzyme hydrolyzing plasma TG at the surface of capillary endothelial cells in adipose tissue [50]. However, reductions in circulating TG and abdominal fat were found in the hypercholesterolemic rats, as compared to controls, which may be associated with an inadequate synthesis of lipoproteins poor in TG and rich in CHOL [51,52].

On the other hand, dietary fat, cholesterol and individual fatty acids differently affect glucose tolerance and utilization [53,54] as well as insulin sensitivity [55]. However, the interactions of a hypercholesterolemic diet on glucose metabolism are often controversial [56,57] and information concerning intracellular events at the liver is still scarce.

In relation to carbohydrate metabolism, serum glucose concentrations were markedly reduced in the hypercholesterolemic animals, which may be due to a reduced supply of carbohydrate in the experimental diet as compared to controls [58]. This situation could also explain the lower levels of plasma insulin in those animals. Thus, reductions of 50% in circulating insulin have been reported in high-fat fed rats and it has been suggested that these diets impair signal transduction mechanisms in pancreatic beta cells to reduce insulin secretion in rats [59] and hence inhibit lipid synthesis in the liver [60].

Moreover, recent reports have indicated that saturated fat and polyunsaturated fatty acids may work together to regulate the expression of several enzymes involved in carbohydrate metabolism [61].

Thus, the reduction in Glc-6-Pase activity in liver suggests that glucose formation is circumvented in order to produce other substrates such as pentoses and glycogen and is in good agreement with the fact that this enzyme may regulate cholesterol synthesis [62].

On the other hand, glucokinase activity and expression are associated with glucose uptake by the liver, in such a way that liver intracellular concentrations below normal decrease the activity of this enzyme [63]. The relatively low supply of glucose by the diet and the requirements for pentose and glycogen formation may explain the values obtained for liver glucokinase activity and glycogen content through a push-pull mechanism for regulation of blood glucose concentration [64]. Furthermore, GK prevents the release of glucose from cell.

In summary, feeding rats on a diet rich in coconut oil and cholesterol for a 26-day period produced important alterations in lipid profile in serum and tissues, as well as modifications in several associated enzymes. Furthermore, our results provide new information about the influence of a diet-induced hypercholesterolemia on carbohydrate metabolism adaptation, in which insulin as well as GK and glc-6-pase in liver are involved. These results stress the role of fat intake on cholesterogenesis, but also the involvement of other metabolic pathways related to carbohydrate utilization.

Thus, the clinical relevance of this feeding trial is to add new clues to understand some previously described facts such as that: a) elevated circulating concentrations of lipids are implicated in the etiology of type 2 diabetes by virtue of their ability to induce insulin resistance and a long-term detrimental action on pancreatic ß-cell function, while a low rate of insulin secretion modulates the extent of the pathologic ketosis and type 1 diabetes [64], and b) the consequences of hypercholesterolemia and altered lipid profiles are to increase the risk of cardiovascular diseases [25].


   ACKNOWLEDGMENTS
 
Financial support from the Tripartite agreement (Aquitania, Basque Country and Navarra Governments) is gratefully acknowledged (Proyecto Nutrición y Salud: 29). Also, we are grateful to Dr. MP. Portillo, Dr. MT. Macarulla, Dr. AS. Barrio, Dr. A. Rocandio and Dr. A. Fernández from the Department of Nutrition of the University of the Basque Country for helpful discussions.

Received February 1, 1998. Accepted June 1, 1998.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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