The Metabolism of Stearic Acid and its Effect on LDL Cholesterol

By Kerianne Hofsiss

For Dr. William R. Proulx, RD Associate Professor of Nutrition & Dietetics

In partial fulfillment for the requirements of

NUTR340 Advanced Nutrition I

November 12, 2013

TABLE OF CONTENTS
I. INTRODUCTION... 2

II. REVIEW OF LITERATURE..

A. Fatty Acids effect on LDL .. B. Metabolism of Stearic Acid .... C. Stearic Acids Neutral effect on LDL-C Effect on absorption ........................ Total Serum Cholesterol levels...

3 3 5 6 7

III. CONCLUSION

IV. REFERENCE LIST .

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INTRODUCTION
Specific fatty acids have been extensively researched for years because of the correlation between high fat diets and cardiovascular disease. For some time it was thought that all fats, unsaturated and saturated were atherogenic. For years research has shown that certain fats; those that raise HDL-C and lower LDL-C are not atherogenic, but are beneficial to the heart. Poly unsaturated and monounsaturated fats were deemed healthy fats while saturated fats were unhealthy and to be limited in the diet. The American diet is higher in saturated fats than many other countries, its also has the highest number of deaths as a result of cardiovascular disease. There is a strong correlation between increased LDL-C and the prevalence of heart disease. For this reason, it is suggested that all saturated fats be limited to less than 10% of fat intake daily. However, stearic acid, an eighteen carbon saturated fatty acid challenges this recommendation. It is unlike other long chain saturated fats in that it does not raise LDL cholesterol. Ahrens et al. in 1957 (1) and Hegsted et al. in 1965 (2) found that stearic acid did not act like other saturated fats in the LDL-C raising action. Since then extensive research has been done on stearic acids neutral effect on LDL-C. This paper will review on stearic acids neutral effect on plasma LDL-C and possible reasons for this property.

REVIEW OF LITERATURE
Fatty acid effect on LDL-C Hayes et al. quantified LDL-C levels in primates by measuring apoB production and clearance rates through use of I125 radiolabeling. Their study showed long chained saturated fatty acids (12:0, 14:0, 16:0) all decreased LDL receptors activity, reducing LDL-C uptake and thus creating higher levels in plasma. Linoleic acid (cis, cis-9, 12 18:2 n-6) was also monitored and found to increase receptor activity thereby suggesting a possible reason for the LDL-C raising effect of saturated fats compared to unsaturated fats neutral/lowering property (3). Fernandez et al also found that hepatic LDL receptor activity was increase along with LDL turnover after increased PUFA intake. Less VLDL was converted to LDL in the PUFA diet resulting in lower LDL cholesterol plasma levels (4). When less VLDL converts to LDL the overall pool of LDL in plasma decreases, since PUFA was also found to increase receptor activity, this results in more receptors available for pick up while having less LDL to be picked up. LDL levels decrease two fold compared to after SFA consumption. It has been accepted that PUFAs decrease LDL and raise HDL while SFAs increase LDL and decrease HDL. Stearic acids neutral effect defies this principal and for that reason requires investigation.

Metabolism of Stearic Acid Stearic acid can be obtained through the diet or synthesized de novo in the body from Acetyl Co-A, which is converted to malonyl-CoA through a reaction catalyzed by acetyl-CoA carboxylase. The FA synthase complex converts malonyl-CoA to palmitate which is elongated into stearate by FA elongases that can either be esterified, elongated, oxidated or desaturated at 3

the -9 position to become oleic acid (cis-9 18:1 n-9) (5). This process is facilitated by the enzyme stearoyl-Coa (SCD1) whose, regulation is dependent on hormones, diet and physiology (6). At low energy, palmitoyl transferase 1 transports stearic acid to the mitochondria for oxidation, which has been found to be influenced by both chain length and number of double bonds. For this reason saturated fatty acids are not as readily oxidized as unsaturated fatty acids (5). Fatty acid oxidation directly influences ketogenesis and metabolism. Without sufficient oxidation of fatty acids, ketones are produced, and glycolysis is used for energy. One study using in vitro hepatocytes showed no preference on oxidation of certain fatty acids within 4 hours of incubation but after 8 hours a preference for oleate oxidation was shown when compared with stearate (7). Thus proposing stearate follows another fate rather than oxidation. Observation of stearate showed other fates such as esterification were also unlikely. Stearate is not a good substrate and is often desaturated to oleate (5). Sampath and Ntambi took a closer look and revealed that esterified stearic acid was not incorporated largely into triglycerides or cholesteryl ester but was used for the synthesis of phospholipids in a human study using stable isotopes. Compared to palmitic acid (16:0) PL synthesis was 40% higher with stearic acid. This may be due to stearic acid being poorly metabolized by acetyl-CoA synthase. Therefore stearate is desaturated to oleate, the preferred substrate, and incorporated into triglycerides which are the most abundant storage form of fatty acids (7). Wang and Koo found similar results by using chylomicrons to inject 14C labeled myristic, linoleic and stearic acid into rats, intravenously. Stearic acid in the liver was accumulating at a higher rate than the others and within 30 minutes was preferentially used for synthesis of phospholipids instead of TAG (8).

Stearic Acids Neutral effect on LDL-C Although other saturated fatty acids raise total serum cholesterol levels, stearic acid does not behave. Several studies have been conducted to decipher the mechanism behind stearic acids neutral effect on LDL-C. In one study, Zock et al. measured serum lipoprotein levels in 26 men and 30 women using multiple fatty acids and found no differences in cholesterol results between stearic acid rich and oleic acid rich diets while myristic, lauric, and palmitic diets all raised LDLC levels (9). They postulate that this is due to the desaturation of stearate to oleate. Unlike palmitic acid, stearic acid does not need to be elongated and is thus converted quicker. When injected with carboxyl-labeled stearic acid, it was found that rats livers recovered 21.9% stearic acid and 8% oleic acid after just 5 minutes revealing that this conversion can be accomplished rapidly within the body (10). Like most monounsaturated fats oleic acid has been found to have little to no effect on LDL-C levels. When levels of oleic acid are high in the liver, cholesterol is quickly esterified as a result of oleic being a preferred substrate for ACAT acyl-CoA: cholesterol acyltransferase. Its been proposed that lowering unesterified cholesterol in the liver may release the suppressive effects on LDL-receptor synthesis associated with the unesterified form of cholesterol. Therefore quicker esterification of oleic acid prevents this suppression from occurring. It has also been found that cell membranes containing higher levels of unsaturated fatty acid enrichment have the potential to increase receptor uptake of LDL from the plasma, these two properties lower LDL levels(6). Since oleate is the preferred substrate for ACAT, and more readily incorporated into TAG and cholesteryl esters, stearate is converted to oleate and thereby takes on LDL neutral/lowering effects associated with oleate. The stable isotope study in humans also revealed that stearic acid was being converted to oleic acid at much higher rates than palmitic and (cis-9 16:1 n-7) palmitoleic acid (7). The ease of the conversion by 5

desaturation of stearic acid to oleic acid, a non-cholesterol raising monounsaturated fatty acid, allows for rapid synthesis of oleic acid. Also elongation of palmitic acid is a longer process and during this time palmitics LDL raising ability is exerted longer (6). Therefore the rapid conversion of stearic acid to oleic acid and oleic acid being a preferred substrate for ACAT are possible reasons for the similar behavior between the two, in regards to their neutral effect on LDL cholesterol. Effect on Absorption The poor absorption of cholesterol in stearic acid rich diets, is another possible explanation for stearic acids neutral effect on plasma LDL cholesterol. A study performed using mice fed diets in tristearin, triolein and safflower oil showed tristearin fed rats as having the lowest absorption level of cholesterol. Rats fed tristearin had 46% absorption while triolein fed was 70% and safflower fed was 75%. Removal of cholesterol from plasma occurred quickest in the tristearin fed rats resulting in lower total plasma cholesterol levels (11). Chen et al also found stearic acid to slow cholesterol absorption. Using rats the researchers injected cholesterol with an emulsion of either maize oil, cocoa butter or palm kernel oil and over 24 hours collected all fatty acids from the thoracic lymph duct of the rats. Cocoa butter being higher in stearic acid was found to have the lowest cholesterol absorption level within the intestine, 63% compared to maize 100% and palm kernel 82% (12). A similar study using trilaurinm trimyristin, tripalmitin and tristearin also resulted in rats having the least amount of cholesterol absorption during tristearin rich diets, rats on this diet also gained less weight during this diet (11). The poor absorption of stearic acid itself has also been proposed as a possible reason for its neutral effect. Lipids obtained through the diet are mostly in the form of triglycerides. Once within the body TGs must be both hydrolyzed and emulsified by bile to be digested and absorbed effectively. 6

Fat is hydrolyzed first in the stomach around 10-30% then moves to the duodenum. Within the small intestine both pancreatic lipase and colipase enzymes hydrolyze at the sn-1 and sn-2 position. The products are free fatty acids and a 2-monoglyceride. Micelles are formed by emulsification and transported to the brush border to be absorbed by facilitated diffusion at the enterocytes (13). Mattson et al. using fats found that stearic acids location on the glycerol backbone greatly affected its absorption. It was found that when located at the sn-2 it was absorbed efficiently. When accompanied by two oleates, and located at either the sn-1 or sn-3 only 55% was absorbed and only 37% absorbed when located at both sn-1 and sn-3 on the glycerol backbone (14). This suggest that the bioavailability of specifically positioned stearic acid on TGs may be a factor. The poor absorption of stearic acid may contribute to it not being able to affect LDL-c as much as other better absorbed SFAs.

Total Serum Cholesterol Levels Cholesterol ester transfer protein regulates HDL-C by transporting cholesterol esters taken from HDL to particles containing apolipoprotein (apo B). VLDL, IDL and LDL receive the HDL cholesterol ester. CETP also initiates the reversal of cholesterol transport from the tissues to the liver. Schwab et al. revealed that stearic acid lowered plasma cholesterol levels more than saturated fatty acids may be a result of it lowering HDL-C levels not just LDL-C. High CETP activity is associated with lower HDL levels and is considered atherogenic. Levels of serum LDL cholesterol and apo B are also increased with higher CETP activity. Schwab et al. measured the CETP activity in plasma in a group of women during periods of stearic acid rich diets and again during palimitc acid rich diets and found higher CETP activity along with total cholesterol

during the palmitic diet compared to stearate. HDL levels were higher in the palmitic diet revealing that CETP activity did not greatly effect HDL levels in this case. This suggests that stearate may contain some other property that causes it to lower HDL levels more than other saturated fats and its lowering effect on cholesterol is not solely attributed to its effect on LDL and should not be associated as being a heart healthy fat. However, the exact effect of CETP activity on HDL is still unclear and requires further research (15).

CONCLUSIONS
Saturated fats have shown to increase LDL plasma cholesterol in the body and are considered atherogenic. LDL receptor activity is reduced after consumption of saturated fats. Lower activity results in a larger LDL pool in plasma. High levels of LDL in plasma is strongly correlated with the incidence of heart disease. Numerous studies have been done on the saturated fat, stearic acid, due to its neutral effect on LDL levels. The research conducted has posed several possible reasons for this behavior. Stearic acid being mal-absorped within the intestine and its inhibition of unesterified cholesterol esters suppressive effects in regards to LDL receptor synthesis were both investigated. CETP activitys effect on both HDL and LDL levels were also observed. These studies provided some evidence for stearic acids neutral effect but were inconclusive. Its been found that the rapid conversion of stearic acid into the monounsaturated fat oleic acid through desaturation, seems to be the most probable reason for its neutral effect on LDL-C levels.

REFERENCE LIST
1. 2. 3. Ahren H. Edward, Insull William, Blomstrand Rolf, et al. The Influence of Dietary Fats on serum-lipid levels in Man. The Lancet. 1957; 1; 943-953 Hegsted DM, McGandy RB, Myers ML, Stare FJ. Quantitative effects of dietary fat on serum cholesterol in man. American Journal of Clinical Nutrition. 1965; 17:281-295 Hayes C. K, Kholsa P, Hajri T, Pronczuk A. Saturated fatty acids and LDL receptor modulation in humans and monkeys. Prostaglandins, Leuokotrienes and Essential Fatty Acids. 1997;V57: 411-418 Fernandez Luz Maria, West L. Kristy, Roy Suheeta, et al. Dietary fat saturation and gender/hormonal status modulate plasma lipids and lipoprotein composition. Journal of Nutritional Biochemistry. 2001; 12: 703-710 Sampath Harini, Ntambi M. James. The Fate and Intermediary Metabolism of Stearic Acid. Lipids. 2005; 40: 1187-1190 Grundy M. Scott. Influence of stearic acid on cholesterol metabolism relative to other longchain fatty acids. American Journal of Clinical Nutrition. 1994;60: 986-989 Bruce S. Jennifer, Salter M. Andrew. Metabolic fate of oleic acid, palmitic acid and stearic acid in culured hamster hepatocytes. Biochem Journal. 1996;316: 847-852 Wang Shu, Koo I. Sung. Evidence for distinct metabolic utilization of stearic acid in comparison with palmitic and oleic acids in rats. The Journal of Nutritional Biochemistry. 1993; 4:594-601 Zock L. Peter, Katan B Martjin. Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans. Journal of Lipid Research. 1992; 33: 399-407

4.

5. 6. 7. 8.

9.

10. Kritchevsky David. Stearic acid metabolism and atherogenesis: history. American Journal of Clinical Nutrtition. 1994; 60: 997-1001 11. Feldman E. B, Russell B. S, Schnare F. H, et al: Effect of tristearin, triolein and safflower oil diets on cholesterol balance in rats. The Journal of Nutrition. 1979; 109: 2226-2236 12. Chen I. S, Subramaniam S, Vahouny G V, et al. A comparison of the digestion and absorption of cocoa butter and palm kernel oil and their effects on cholesterol absorption in rats. The Journal of Nutrition. 1989; 119: 1569-1573 13. Etherton- Kris M. Penny, Griel E. Amy, Psota L. Tricia, et al. Dietary Stearic Acid and Risk of Cardiovascular Disease: Intake, Sources, Digestion, and Absorption. Lipids. 2005; 40: 1193-1200 10

14. Mattson F. H, Nolen G. H, Webb M. R. The absorbability by rats of various triglycerides of stearic and oleic acid and the effect of dietary calcium and magnesium. The Journal of Nutrition. 1979;109;1682-1687 15. Schwab S Ursula, Maliranta M Helvi, Sarkkinen S Essi, et al: Different Effects of Palmitic and Stearic Acid-Enriched Diets on Serum Lipids and Lipoproteins and Plasma Cholesteryl Ester Transfer Protein Activity in Healthy Young Women. Metabolism. 1996; V45:143-149

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