Dietary zinc deficiency and fatty acid metabolism in rats

Dietary zinc deficiency and fatty acid metabolism in rats

Nutrition Research, Vol. 16. No. 7, pp. 11794189, 1996 Copyright Q 1996 Ekvier Science Inc. Printed in the USA. All rights reserved 0271~5317/96 $15.0...

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Nutrition Research, Vol. 16. No. 7, pp. 11794189, 1996 Copyright Q 1996 Ekvier Science Inc. Printed in the USA. All rights reserved 0271~5317/96 $15.00 + .OO

PII SO271-5317(96)00122-4

ELSEVIER

DIETARY ZINC DEFICIENCY

AND FATTY ACID METABOLISM

K. Eder (Dr. Dr. habil) and M. Kirchgessnerl

IN RATS

(Prof. Dr. Dr. h.c.mult)

Institut fiir Emihrungsphysiologie Technische UniversitZit Miinchen-Weihenstephan,

D-85350 Freising, Germany

ABSTRACT Several clinical features of zinc deficiency fatty acid deficiency

suggesting

in rats are similar to those of essential

a role of zinc in fatty acid metabolism.

find out the role of zinc in fatty acid metabolism,

In order to

several zinc deficiency studies in

rats have been carried out. The results of those studies are reviewed in this paper with respect to the effects of zinc deficiency on the desaturation incorporation composition

of polyunsaturated of erythrocyte

of fatty acids, the

fatty acids into tissue lipids and the fatty acid

membranes.

Zinc deficiency

zinc plays a role in AS and A6 desaturation

experiments

indicate that

although there are some reports that did

not support such a function of zinc. The effects of zinc deficiency on A9 desaturation are contradictory. desaturation, deficient

Some

results

suggested

rats contained

higher amounts

lower amounts of (n-6) polyunsaturated influences

the incorporation

contrast, zinc deficiency erythrocyte

that zinc

deficiency

while others suggested reduced A9 desaturation.

membranes.

of (n-3) polyunsaturated fatty acids, suggesting

of polyunsaturated

increased

Phospholipids

fatty acids and

that zinc deficiency

fatty acids into phospholipids.

In

had only slight effects on the fatty acid composition

of

Consequences

of changes in fatty acid metabolism

deficiency may include synthesis of eicosanoids and properties of membranes. Key words: Zinc deficiency, fatty acids, rat, phospholipids,

korresponding

A9

of zinc

author

1179

desaturation

by zinc

1180

K. EDER and M. KIRCHGESSNER

INTRODUCTION It has been shown that several clinical features of zinc deficiency in rats are similar to those of essential fatty acid (EFA) deficiency. These include growth reatardation, dermal lesions, immunodeficiency, alopecia, male and female infertility and increased capillary permeability (1). Moreover, zinc deficiency has been shown to accentuate symtoms of EFA deficiency (2). Those observations suggest a role of zinc in the metabolism of EFA. In order to find out the role of zinc in EFA metabolism, several zinc deficiency experiments have been carried out examining the effect of zinc deficiency on fatty acid composition of tissue lipids and the activities of fatty acid desaturases in rats. The present paper reviews results about the effect of zinc deficiency on fatty acid metabolism in rats. ZINC DEFICIENCY

AND A5 AND A6 DESATURATION

EFAs belong to two families, those with the (n-6) configuration and those with the (n-3) configuration. The parent fatty acids are linoleic acid (l&2 n-6) and a-linolenic acid (l&3 n-3). To fulfill their functions, EFA have to be desaturated and elongated to long-chain higher unsaturated fatty acids. A6 desaturase converts linoleic acid (l&2 n-6) into y-linolenic acid (18:3 n-6) and (Ylinolenic acid (l&3 n-3) into octadecatetraenoic acid (18:4 n-3). After an elongation step, A5 desaturase forms the biological more important fatty acids, arachidonic acid (20:4 n-6) and eicosapentaenoic acid (20~5 n-3). Those fatty acids serve as precursors for eicosanoids and are of primary importance as constituents of biological membranes (3, 4). Results on A5 and A6 desaturation derive either from data about fatty acid composition of lipids, particularly phospholipids from tissues or from measurements of activities of desaturase enzymes. Indices commonly used for assessment of A5 and A6 desaturase are levels of linoleic acid and arachidonic acid and their ratio as well as products derived from A6 desaturation (l&3 n-6 and 20:3 n-6) and A5 desaturation (20:4 n-6 and 22:4 n-6) in phospholipids, particularly in hepatic phospholipids. Zinc deficiency experiments commonly include three groups of rats, a zinc-deficient group and two control groups, one fed the diet ad-libitum, another pair-fed the control diet to the zincdeficient group. The pair-fed control group controls for the reduced food intake caused by zinc deficiency. Hence, the effects of zinc deficiency commonly are examined by comparing zincdeficient rats with pair-fed control rats. Table 1 summarizes the effect of zinc deficiency on levels of linoleic acid and arachidonic acid in liver and plasma lipids of rats. The phospholipid fraction is most commonly analyzed for assessing desaturation because this fraction contains a large portion of the highly unsaturated fatty acids derived from linoleic acid and cr-linolenic acid by desaturation. The Table demonstrates that the results reported in literature are contradictory. Impaired A5 and A6 desaturation would be expected to increase levels of linoleic acid and lower levels of arachidonic acid in phospholipids (5). There are a few studies reporting changes in the fatty acid composition indicating impaired desaturation in zinc-deficient rats (6-11). However, fatty acid data reported from several other studies do not support an impaired A5 and A6 desaturation (11-19). Some studies investigated the effect of zinc deficiency on fatty acid corn osition of total lipids from rat tissues (19-23). However, it should be noted that the pool size o ! triglycerides influences ita fatty acid composition (24), and thus the fatty acid composition of total lipids depends on the ratio between triglycerides and phospholipids. Increased levels of arachidonic acid found in total hepatic lipids of zincdeficient rats might be due to decreased concentrations of triglycerides in liver of zinc-deficient rats (8). Since previously published fatty acid composition data fail to give a consistent picture of the effect of zinc deficiency on fatty acid desaturation, some investigators have measured activities of A5 and A6 desaturases in tissues of zinc-deficient rats. The results are summarized in Table 2. In weanling rats, most of the studies demonstrated reduced A5 and A6 desaturation in tissues of zincdeficient rats. The effect of zinc deficiency on desaturation may be influenced by dietary fat patterns. Tsai et al. (25) reported that subcutaneous injection of safflower oil, but not evening primrose oil, normalized A6 desaturase which was initially lowered in zincdeficient rats. In rarpd fat-free diets, Kudo et al. demonstrated increased desaturation of intravenously injected Clinoleic acid (17). In rat fetuses, but not in their mothers, zinc deficiency lowered hepatic A6

ZINC AND FAll-Y ACID METABOLISM

1181

desaturation (11, 18). Finally, in mammary glands of lactating rata, zinc deficiency even increased A6 desaturation (16) indicating that the effect of zinc deficiency may depend on the tissue and the physiological state of the animals. The reduced food intake in rats fed a zinc-deficient diet is a serious problem because zincdeficient and pair-fed control rats have a general deficiency in nutrients and energy, which in particular may affect the lipid metabolism. Therefore, in order to overcome this problem some investigators have fed zinc-deficient and control diets by gastric tube (26-29). The disadvantage of this feeding technique is that the experiment has to be terminated after 10 to 12 days, limiting this technique to investigation of the effects of short-term zinc deficiency. The effect of zinc-deficiency on fatty acid desaturation in force-fed rats has been investigated using different types of dietary fat based either predominately on coconut oil, fish oil or linseed oil (30-35). With all types of dietary fats, zinc deficiency did not change the fatty acid composition of phospholipids from several tissues in the way consistent with impaired A5 and A6 desaturation. In agreement with fany acid composition data, activities of A5 and A6 desaturases from hepatic microsomes were not changed by zinc deficiency in rats force-fed either a diet with predominately coconut oil or linseed oil as dietary fat (34). However, when a fat-free diet was adminstered initially for six days, and thereafter safflower oil was supplemented, zinc deficiency suppressed the conversion of linoleic acid into arachidonic acid, docosatetraenoic acid and docosapentaenoic acid (Table 3). This result indicates that zincdeficiency impairs desaturation of linoleic acid in force-fed rats when the basal activities of desaturases are raised by feeding initially fat-free diets. A recent study by Yang and Cunnane (36) also demonstrated decreased desaturation of linoleic acid and a-linolenic acid in pregnant rats force-fed a marginal zinc-deficient diet. Possible consequences of an impaired deaaturation of linoleic acid may concern synthesis of eicosanoids which derive from C20polyunsaturated fatty acids (PUFA). Zinc deficiency in the pregnant rat has been shown to produce similar pathological symptoms to those with the administration of acetylsalicylic acid (37), which may be related to impaired EFA metabolism. The skin lesions seen in zinc deficiency are very similar to those seen in animals with EFA deficiency, suggesting that they, too, are associated with an altered prostaglandin synthesis. It was found that skin lesions due to EFA deficiency were aggravated by simultaneous zinc deficiency (2) but improved by cutaneous administration of prostaglandin E2 (37). Another possible consequence of impaired fatty acid desaturation may concern properties of membranes. The fatty acid composition of membrane phospholipids is a major determinant of membrane fluidity and therefore, influences important parameters such as fragility, permeability and activities of membrane-bound enzymes (38). Zinc deficiency has been shown to influence the fluidity of membranes which may be connected with changes in the lipid and fatty acid composition (39). ZINC DEFICIENCY

AND A9 DESATURATION

The effect of zinc deficiency on A9 desaturation has been less intensively investigated than that on A5 and A6 desaturase. A9 desaturation can be assessed by the ratio between saturated and monounsaturated fatty acids in tissue lipids or by measuring the activity of A9 desaturase in microsomes. Table 4 summarizes results from classical zinc deficiency experiments about levels of stearic and oleic acid in liver lipids of rats. While impaired A9 desaturation might be expected to increase levels of stearic acid and lower levels of oleic acid in tissue lipids (5), the effect of zinc deficiency on levels of those fatty acids in lipids is contradictory. The levels of stearic acid were unchanged or increased, the levels of oleic acid in most cases were unchanged. Thus regarding tissue fatty acid composition data, a few reports (13, 17. 21, 23) indicated impaired A9 desaturation in zinc-deficient rats whereas results from others (6, 10, 11, 12, 18) did not support reduced A9 desaturation. The activity of A9 desaturase in liver microsomes has been reported to be increased in zinc-deficient rats from classical zinc deficiency experiments (6, 40). However, in contradiction w’th those results in r ts fed a fat-free diet zinc deficiency suppressed the in vivo conversion of 14C-stearic acid into 1l C-oleic acid indicating reduced A9 desaturation (17). In force-fed rats, zinc-deficiency has been shown to impair A9desaturation. The activity of A.Pdesaturase in liver microsomes was lowered by zincdeficiency in rata fed either a coconut oil diet or a linseed oil diet (34). In agreement with decreased activities of A9-desaturase in zinc-

K. EDER and M. KIRCHGESSNER

1182

deficient rats the levels of stearic acid in liver phospholipids were higher in zinc-deficient rats and those of oleic were lower than in zinc-adequate rats fed different types of dietary fat (Table 5). Possible consequences of impaired A9 desaturation in zinc-deficient individuals may concern membrane properties since monounsaturated fatty acids bound in membrane phospholipids also influence the fluidity of membranes (3). TABLE 1 Results from Classical Zinc Deficiency Experiments on the Effect of Zinc Deficiency on the Levels of Linoleic Acid and Arachidonic Acid in Rat Tissues Tissue

Lipid Fraction

Linoleic Acid

Arachidonic Acid

Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver microsome Liver microsome Liver microsomes# Liver microsomes+ Plasma+ Plasma+ Plasma+ Plasma+ Plasma+ Plasma*

Total Total Total Total Total Total Total PE Total Total Total PC

no change no change no change no change increase increase increase no change no change no change no change no change no change no change increase no change increase increase no change no change increase

decrease increase no change no change increase no change decrease increase increase increase no change no change decrease decrease decrease no change decrease decrease decrease no change decrease

;sl Total Total Total PC PS Total Total

phospholipids phospholipids phospholipids phospholipids phospholipids phospholipids phospholipids lipids lipids lipids

lipids phospholipids phospholipids lipids lipids

+ weaned rats, * adult rats, 0 pregnant rats, # rat fetuses. Abbreviations: PE, phosphatidylethanolamine; PS, phosphatidylserine

Ref.

t::j $2 (9) $:I # i::j (11) (6) I::; $j [:$

PC, phosphatidylcholine;

TABLE 2 Results from Classical Zinc Deficiency Experiments on the Effect of Zinc Deficiency on Activities of A5- and A6-Desaturase in Rat Tissues Animals

Tissue

Weanling rats

Liver Liver Liver Testes Liver Mammary gland Liver

Pregnant rats Lactating rats Rat fetuses n.d. = not determined

A5 desaturase

Ref.

decrease no change decrease decrease

decrease decrease n.d. decrease

($j

no change increase decrease

n.d. n.d. n.d.

[::I (11)

A6 desaturase

ZINC AND FAlTY ACID METABOLISM

1183

TABLE 3 Conversion of Linoleic Acid into Higher Unsaturated Fatty Acids in Zinc-adequate and Zincdeficient Rats Initially Force-fed a Fat-free Diet for 6 days and thereafter Supplemented with Sufflower Oil (Levels, %, by Mol of (n-6) Polyunsaturated Fatty Acids in Liver Phospholipids, from Ref. 35) Treatment

l&2

20:3

20:4

224

22:s

Phosphatidylcholine Zinc-adequate Zinc-deficient

10.9, 12.3

I::*

23.5 17.4*

0.6 0.5*

2.7 1.5*

Phosphatidylethanolamine Zinc-adequate Zincdeficient

4.0 4.7*

::;*

28.1, 25.1

1.0 0.8*

5.6 3.3*

Phosphatidylserine Zinc-adequate Zincdeficient

if:::

g:;*

1.1 1.3,

3.4 3.5

*Statistical significant

1.2 1.7*

(p-zO.05) difference

TABLE 4 Results from Classical Zinc Deficiency Experiments on the Effect of Zinc Deficiency on the Levels of Stearic Acid (l&O) and Oleic Acid (18: 1 n-9) in Rats Tissue

Lipid Fraction

Stearic acid

Oleic acid

Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver+ Liver microsomes# Liver microsomes# Liver microsomes+

Total Total Total Total

increase no change no change increase no change increase no change increase increase no change no change increase

decrease no change no change decrease no change no change no change decrease no change no change no change increase

:: Total Total Total PC PS Total

phospholipids phospholipids phospholipids phospholipids lipids lipids lipids lipids

+ weaned rats, # rat fetuses. Abbreviations: ethanolamine; PS, phosphatidylserine

PC, phosphatidylcholine;

PE, phosphatidyl-

Ref.

K. EDER and M. KIRCHGESSNER

1184

TABLE 5 Levels of Steak Acid (18:0) and Oleic Acid (18: 1, %, by Mol) and the Ratio Between those Fatty Acids in Liver Phosphatidylcholine of Zinc-adequate (Zn+) and Zinc-deficient (Zn-) Force-fed Rats (from Refs 30,32,33,34) Exp. Dietary Fat

18:l

18:0

18:0/1&l

Zn+

Zn-

Zn+

Zn-

Zn+

;

Coconut oil1 Coconut oil1

16.5 16.3

20.3* 23.2*

10.3 10.5

: 5 6

Salmon oil Coconut oi kl Linseed oil Linseed oil

14.6 16.8 15.8 16.6

21.2* 21.7* 20.0* 21.0*

11.0 9.6 8.9 9.2

11.3, 8.1, ;i*

1.60 1.55 1.33 1.75 1.78 1.80

*statistical significant difference (pqO.05); lCoconut oil/safflower oil mixture (lO:l, w/w)

ZINC DEFICIENCY AND THE INCORPORATION INTO PHOSPHOLIPIDS

7:7* 8.0*

Zn* kE* 2:36* 2.93* 2.60* 2.63*

oil/safflower oil mixture (7:1, w/w); 2Salmon

OF POLYUNSATURATED

FATTY ACIDS

Most of the long-chain highly unsaturated fatty acids originating from desaturation of linoleic acid and a-linolenic acid are incorporated into membrane phospholipids. Studies with force-fed rats suggest that zinc deficiency influences the incorporation of PUFA into phospholipids, particularly into phosphatidylcholine (30, 32-34). Liver phosphatidylcholine from zinc-deficient force-fed rats contains higher levels of (n-3) fatty acids and lower levels of (n-6) PUFA than that from zincadequate force-fed rats. This effect was most pronounced when fats with high levels of (n-3) PUFA such as linseed oil or fish oil were used as source of dietary fat (Table 6). In this case there was considerable accumulation of eicosapentaenoic acid in zinc-deficient rats. But even when a coconut oil/safflower oil mixture was used, levels of (n-3) PUFA were elevated and levels of (n-6) PUFA were lowered in zincdeftcient rats. In this case accumulation of (n-3) PUFA was based mainly on docosahexaenoic acid. In phosphatidylethanolamine the shift between (n-6) and (n-3) PUFA in zinc-deficient rats was less pronounced. Apart from that shift which occurs particularly in phosphatidylcholine, rats force-fed zinc-deficient diets with various types of dietary fat also exhibited lower levels of linoleic acid in all types of phospholipids (30-34). A recent study from Yang and Cunnane (36) using l4 C-linoleic acid suggests that this effect is due to enhanced oxidation of linoleic acid in zincdeficient rats. Changes in the levels of polyunsaturated fatty acids, particularly a shift in the ratio between arachidonic acid and eicosapentaenoic acid may have important implications on synthesis of eicosanoids. A decreased ratio between arachidonic acid and eicosapentaenoic acid suggests that the synthesis of diene prostaglandins is reduced and that of triene prostaglandins is increased. The effects of triene prostaglandins are in some respects very different from those of diene prostaglandins. For instance, triene prostaglandins inhibit blood coagulation and thrombocyte aggregation to a greater extent than diene prostaglandins (4).

ZINC AND FATTY ACID METABOLISM

1185

TABLE 6 Levels of (n-6) and (n-3) Polyunsaturated Fatty Acids (PUFA, %, by Mol) in Liver Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE) of Zinc-adequate (Zn+) and Zincdeficient (Zn-) Force-fed Rats (from Refs 3233) Dietary Fat

Lipid

X(n-6) PUFA

s(n-3) PUFA

x(n-6)&i-3)

Zn+

Zn-

Zn+

Zn-

Zn+

Zn-

Coconut oil1

PC PE

33.0 33.1

30.6* 29.7*

6.4 13.1

7.8* 14.8*

5.16 2.53

3.92* 2.07*

Salmon oil2

PC PE

18.0 11.9

13.0* 9.6*

25.0 34.4

29.5* 35.3

0.72 0.35

0.44* 0.27*

26.5 18.1

21.9* 16.9*

17.8 31.3

22.7* 31.3

1.49 0.58

0.96* 0.54

Linseed oil

*statistical significant difference (pdO.05); lCoc.onut oil/safflower oil mixture (7:1, w/w); 2Salmon oil/safflower oil mixture (lO:l, w/w)

ZINC DEFICIENCY MEMBRANES

AND

THE

FATTY

ACID

COMPOSITION

OF

ERYTHROCYTE

Zinc has been proposed to have a critical role in the structure and function of biomembranes (41, 42). Particular in erythrocytes, zinc deficiency affects membrane properties such as its osmotic fragility (43-45). Since the fatty acid composition of phospholipids influences important membrane properties (3), some studies have been carried out to investigate the effect of zinc deficiency on the fatty acid composition of erythrocyte membrane phospholipids (48-51). Classical zinc deficiency experiments have shown that zinc deficiency has only slight effects on the fatty acid composition of erythrocyte membrane phospholipids (48-51). The most pronounced changes concerned the levels of (n-3) PUFA which were elevated in zinc-deficient rats (48-5 1). In contrast, levels of saturated, monounsaturated and (n-6) polyunsaturated fatty acids were negligibly affected by zinc deficiency (48-51). In studies with force-fed rats, the effect of zinc deficiency on the fatty acid composition of erythrocyte membranes was slightly, too (52-54). Those studies have shown that the most pronounced effects of zinc deficiency occur in phosphatidylcholine. In that phospholipid, zinc deficiency caused elevated levels of saturated fatty acids, particularly stearic acid, decreased levels of (n-6) PUFA, particularly linoleic acid and increased levels of (n-3) PUFA (52-54). These changes were reproduced with different types of dietary fat, and thus may be typical for phosphatidylcholine. In contrast, in phosphatidylethanolamine and phosphatidylserine, the effects of zinc deficiency depended on the dietary fat. When a coconut oil/safflower oil mixture was used, the main effect of zinc deficiency in those phospholipids were increased levels of (n-3) PUFA, particularly of docosahexaenoic acid (52). When fish oil was used, the levels of total (n-3) PUFA were not changed; however, the ratio between individual (n-3) PUFA was changed by zinc deficiency (54). When linseed oil was used, there was even a slight decrease in (n-3) PUFA in phosphatidylethanolamine and phosphatidylserine in zinc-deficient rats (53). The fatty acid composition of sphingomyelin regardless of the dietary fat was not influenced by zinc deficiency (52-54). Since zinc deficiency has only slight effects on the fatty acid composition of erythrocyte membrane phospholipids, it is likely that most of the effects of zinc deficiency on membrane properties are not mediated by a changed fatty acid composition (48, 51). This is also evident by a study (48) showing that upon re-feeding zinc the osmotic fragility of erythrocytes returns to normal

K. EDER and M. KIRCHGESSNER

1188

more rapidly than the fatty acid composition of membrane phospholipids. Other studies have shown that although the effect of zinc deficiency depends on the type of dietary fat, zinc deficiency increases the osmotic fragility of erythrocytes regardless of the dietary fat (53, 54). Therefore, it is likely that zinc as a structural component stabilizes membranes or alternatively is component of an antioxidant compound which protects sulfhydryl groups in membranes against oxidation (44, 46, 47, 48, 55). CONCLUSION Experiments in rats clearly show that zinc deficiency affects the fatty acid metabolism in several ways although results reported in literature are not consistent. Classical zinc deficiency experiments have the disadvantage that some effects of zinc deficiency are confounded by the reduced food intake. Experiments with force-fed rats are useful in overcoming this problem; however, their drawback is that they are limited to the short-term examination of the effects of zinc deficiency. Nevertheless, both types of experiments suggest that zinc plays a role in the desaturation of EFA and possibly also in the desaturation of saturated fatty acids. Additionally, zinc deficiency may affect the incorporation of PUFA into tissue lipids, and thus influences the fatty acid composition of membranes. Those changes in fatty acid metabolism may have important physiological consequences such as an altered synthesis of prostaglandins and altered membrane properties including fluidity, permeability, fragility and activities of membrane bound enzymes. Hence, the changes in fatty acid metabolism contribute to the large picture of physiological abnormities and clinical symptoms caused by zinc deficiency. ACKNOWLEDGMENT A part of the studies from Eder and Kirchgessner gemeinschaft

was supported by the Deutsche Forschungs-

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