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Department of Pediatrics University of South Florida Tampa, FL 33606-3309
Dear Editor:
Using the techniques of molecular biology Steven Clarke (1
) and his colleagues (2
) demonstrated that the polyunsaturated fatty acids (PUFA) regulate genes that affect the metabolic pathways that partition fatty acids between storage and oxidation. In the process of developing this hypothesis, Clarke has cast new light on an old problem.
In 1952, Kinsell et al. (3
) and Groen et al. (4
) independently demonstrated that the isoenergetic substitution of vegetable oils for animal fats significantly decreased serum cholesterol in humans. In 1957, Ahrens (5
) and Keys et al. (6
) showed that linoleic acid was more potent than oleic acid in causing this response. Early studies to clarify the mechanism of PUFA action on serum cholesterol by studying the absorption, metabolism and storage of cholesterol in animals and humans led to contradictory and primarily negative results. (7
,8
)
In 1963, Nestel and Steinberg (9
) compared the metabolism of palmitic and linoleic acids in rat liver slices and in the isolated perfused rat liver. They observed that palmitate was preferentially synthesized into triglycerides, whereas linoleate was channeled mainly into oxidative pathways. Bjorntorp (10
) then showed that rat liver mitochondria oxidized linoleate faster than other common fatty acids. This led us to believe that the hypocholesterolemic action of linoleate was due principally to changes in its metabolism rather than changes in cholesterol metabolism. We undertook to test this hypothesis in humans.
In 1967, Nichaman et al. (11
,12
) reported the results of a study of the metabolism of linoleate-1-14C in two normolipemic and two hyperlipemic humans fed diets containing 4 and 18% of energy as linoleic acid, respectively. Each patient was fed the two diets sequentially for 4 wk each. A tracer dose of isotopic linoleate was given by mouth at the end of wk 3, and radioactivity measured in the plasma lipids and respiratory CO2 during the ensuing 48 h. The two normolipemic subjects had a normal lipoprotein profile, whereas the two hyperlipemic patients had high concentrations in plasma VLDL and total plasma triglycerides > 1000 mg/dL (11.6 mmol/L). Changing the dietary linoleate from 4 to 18% of energy reduced plasma triglycerides 
30% in the normal subjects and 52% in the hyperlipemic subjects. Furthermore, the fractional turnover constant of plasma triglycerides in the hyperlipemic subjects was increased from 0.025/h to 0.410/h. Moreover, when 18% linoleate diets were consumed, the conversion of linoleate to CO2 increased in all subjects, an average of 2.9-fold in the normal subjects and 4.6-fold in the hyperlipemic patients. From these data, we concluded that "high linoleate feeding may contribute to the control of hyperlipemia by diverting more dietary fatty acid toward oxidative pathways, thus leaving less for hepatic biosynthesis of low-density lipoproteins."
This evidence that linoleate reduces plasma lipoproteins by directing fatty acid metabolism away from synthesis and toward oxidation has not been generally accepted by the scientific community (13
) although Beynen and Katan gave this idea a plug in 1985 (14
).
Recent advances in molecular biology have revealed that a variety of nutrients can affect gene expression and thereby modify metabolic events. These include metabolites of vitamin A and vitamin D, several trace minerals, cholesterol and now the PUFA. It is of great interest that PUFA down-regulate genes that control fatty acid and cholesterol synthesis [acetyl-CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase and the sterol regulatory element binding protein (SREBP)] and up-regulate genes associated with fat oxidation [carnitine palmitoyl transferase and peroxisome proliferator–activated receptor 
(PPAR)].
The so-called "metabolic syndrome" consists of overweight, insulin resistance, hypertriglyceridemia, low plasma HDL and hypertension. (15
) Clarke (1
,16
) makes the point that the genetic regulatory effects of PUFA may protect against the adverse signs of the metabolic syndrome by inhibiting fat storage and promoting fat oxidation. The purpose of this letter is to indicate that his findings on the genetic effects of PUFA have also contributed to an explanation for the long-established effect of PUFA on serum cholesterol levels in otherwise healthy persons.
In summary, the recent discovery of the genotrophic actions of PUFA has explained the effects of linoleate feeding in both animals and humans in studies carried out long ago. It should be the aim of investigators currently studying the role of genetic regulation of metabolic events to couple these mechanistic studies with clinical investigations of related metabolic diseases. A good place to start would be to study the effect of dietary linoleate on subjects with the "metabolic syndrome."
Manuscript received 11 July 2001. Revision accepted 6 October 2001.
LITERATURE CITED
1.
Clarke, S. D. (2001) Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome. J. Nutr. 131:1129-1132.
2. Jump, D. B. & Clarke, S. D. (1999) Regulation of gene expression by dietary fat. Annu. Rev. Nutr. 19:63-90.[Medline]
3. Kinsell, L. W., Partridge, J., Boling, L., Margen, S. & Michaels, G. (1952) Dietary modification of serum cholesterol and phospholipid levels. J. Clin. Endocrinol. 12:909-928.
4. Groen, J., Tijong, B. K., Kamminga, C. E. & Willebrand, A. F. (1952) Influence of nutrition, individuality and some other factors, including various forms of stress on the serum cholesterol: an experiment of nine months duration in 60 normal volunteers. Voeding 13:556-590.
5. Ahrens, E. H. (1957) Nutritional factors and serum lipid levels. Am. J. Med. 23:928-948.
6. Keys, A., Anderson, J. T. & Grande, F. (1957) Prediction of serum cholesterol response of man to changes in fats in the diet. Lancet ii:959-962.
7. Grundy, S. M. & Ahrens, E. H. (1970) The effects of unsaturated dietary fats on absorption, excretion, synthesis and distribution of cholesterol in man. J. Clin. Investig. 49:1135-1152.
8. Paul, R., Ramesha, C. S. & Ganguly, J. (1970) On the mechanism of hypocholesterolemic effects of polyunsaturated lipids. Adv. Lipid Res. 17:155-171.
9. Nestel, P.J. & Steinberg, D. (1963) Fate of palmitate and linoleate perfused through the isolated rat liver at high concentrations. J. Lipid Res. 4:461-469.[Abstract]
10.
Bjorntorp, P. (1968) Rates of oxidation of different fatty acids by isolated rat liver mitochondria. J. Biol. Chem. 243:2130-2133.
11. Nichaman, M. Z., Sweeley, C. C. & Olson, R. E. (1967) Plasma fatty acids in normolipemic and hyperlipemic subjects during fasting and after linoleate feeding. Am. J. Clin. Nutr. 20:1057-1069.[Abstract]
12. Nichaman, M. Z., Olson, R. E. & Sweely, C. L. (1967) Metabolism of linoleic acid-1-14C in normolipemic and hyperlipemic humans fed linoleate diets. Am. J. Clin. Nutr. 20:1070-1083.[Abstract]
13. National Research Council (U.S.) Committee on Diet and Health (1989) Evidence on Dietary Components and Chronic Diseases in Diet and Health 1989:178-192 National Academy Press Washington, DC. .
14.
Beynen, A. C. & Katan, M. B. (1985) Why do polyunsaturated fatty acids lower serum cholesterol?. Am. J. Clin. Nutr 42:560-563.
15. Reaven, G. M., Chen, Y.-D.I., Jeppesen, J., Maheux, P. & Krauss, R. M. (1993) Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J. Clin. Investig. 92:141-146.
16. Clarke, S.D. (2000) Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance. Br. J. Nutr. 8(suppl. 1):S59-S66.
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