Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism
Dietary cholesterol and the activity of stearoyl CoA desaturase in rats: evidence for an indirect regulatory effect
Introduction
Stearoyl CoA desaturase (SCD) is a microsomal enzyme that catalyzes the conversion of long-chain saturated fatty acyl CoAs (primarily 16:0 and 18:0) to monounsaturated acyl chains (16:1n-7 and 18:1n-9). Oleic acid, the predominant unsaturated fatty acid in the cell, is the major product of this reaction.
Previous work in this laboratory demonstrated that a 10% corn oil/1% cholesterol diet altered the fatty acid composition of liver plasma membrane of rats fed for four weeks compared to rats fed a 10% corn oil diet [1]. Both oleic acid and palmitoleic acid increased 2-fold in the membrane. Furthermore, the total percentage of oleic acid and stearic acid was constant in liver plasma membranes between the two groups of animals [1].
Leikin and Brenner fed rats similar diets containing either 13% corn oil or 13% corn oil/1% cholesterol/0.5% cholic acid [2]. These investigators measured the activity of SCD after 48 h and 21 days of feeding. Liver microsomes from rats fed cholesterol for 48 h demonstrated an approx. 50% higher SCD activity than the microsomes from control rats. After 21 days of cholesterol feeding, SCD activity was 4-fold higher than in the control-fed [2]. Interestingly, with either corn oil-based diet, Leikin and Brenner reported decreased SCD activity between 48 h and 21 days of feeding, although to a lesser extent in the cholesterol-fed rats.
SCD activity has been reported previously to decrease with corn oil feeding 3, 4. The mechanism has been reported as a decreased rate of SCD1 gene transcription by feeding different types of fats 5, 6. A 10% safflower oil diet, containing approx. 73% linoleic acid, largely suppressed the expression of SCD mRNA in the liver after four days of feeding compared to the fat-free diet [6]. However, the 10% cocoa butter diet, containing approx. 60% stearic acid, did not reduce SCD message, while the 10% olive oil diet (approximately 70% oleic acid) produced only a slight reduction. Synthetic triacylglycerols (at 3.3% of the diet) demonstrated similar effects on the expression of hepatic SCD mRNA [6]. The suppression of SCD mRNA with trilinolein feeding was found to be due to repression of the transcription of the SCD gene as measured by nuclear run-on experiments [6]. Others have reported that the transcription of the hepatic SCD1 gene and the induction of the hepatic SCD1 mRNA increased from 2-fold after 6 h to 45-fold after 36 h when mice were fasted 24 h and then refed a fat-free, high carbohydrate diet [5]. The SCD mRNA decreased rapidly within 24 h of being switched to a chow diet [5]. Thus, the decrease in SCD activity seen over time with polyunsaturated fat (corn oil) feeding can be explained as the repression of the SCD gene by polyunsaturated fats. This does not, however, explain the difference in SCD activity with cholesterol feeding. Leikin and Brenner hypothesized that increased SCD activity was caused by a decrease in membrane fluidity that follows cholesterol intake [2]. These researchers proposed that the decrease in fluidity `stabilized' the components of the SCD complex and increased its activity. The reported increase in the cholesterol:phospholipid ratio, decrease in fluidity in the liver microsomes and increase in SCD activity demonstrates a correlation, and not necessarily a mechanistic relationship. A more in-depth investigation of the time course for cholesterol incorporation into the membrane and SCD activity changes would aid in elucidating this relationship.
The two genes which encode the SCD enzyme in the mouse (and rat), SCD1(I) and SCD2(II), are expressed and regulated differently in various tissues. SCD1 mRNA is expressed constitutively in adipose tissue, is inducible in the liver and to a lesser extent in kidney and lung, and is absent in brain, heart and spleen [7]. SCD2 mRNA encodes a protein of 358 amino acids with >87% sequence identity to SCD1. SCD2 mRNA is constitutively expressed in the brain, and its expression in kidney, adipose and lung tissue is greatly increased by feeding mice a fat-free diet. SCD2 mRNA is not expressed in the liver regardless of the dietary conditions, but is present at low levels in heart and spleen [7]. The effect of cholesterol on SCD has only been investigated in the liver. Therefore, the level of SCD mRNA of various tissues from rats fed either corn oil or corn oil/cholesterol diet will be determined.
Thus, we investigate the hypothesis that cholesterol attenuates SCD activity in the liver by stabilizing the endoplasmic reticular membranes.
Section snippets
Animals and diets
Sprague–Dawley male rats (Taconic Farms, Germantown, NY) were obtained when they weighed approx. 120 g (∼5 weeks). Rats were housed individually in stainless steel wire-bottom cages on a 12-h light/dark cycle and allowed free access to non-purified diet (Ralston Purina, St. Louis, MO) and water for at least four days upon delivery. All animal procedures were reviewed and approved by the Rutgers Small Animal Care Committee. Rats were then fed either a 10% corn oil (CO) or a 10% corn oil/ 1%
Plasma and liver cholesterol values
Total plasma and liver cholesterol values were determined from rats fed CO or CO/CH diets for one, three, or seven days. Liver cholesterol values are illustrated in Table 1. Liver total cholesterol was significantly increased at every time point with cholesterol feeding. Cholesterol feeding elevated total liver cholesterol by 66.5%, 65.2% and 636.7% after one, three and seven days, respectively. Plasma total cholesterol values did not differ significantly at any time point and averaged 58 mg/dl.
Discussion
Our initial intention in this study was to investigate the hypothesis of Leikin and Brenner that the cholesterol-induced increase in SCD activity is due to membrane stabilization [19]. Cholesterol insertion into the microsomal membrane was proposed as the stimulus for the increased SCD activity with subsequent oleic acid addition to compensate for the decrease in fluidity [19]. In our experiments, SCD activity was higher with cholesterol feeding at 3 days (Fig. 1) while the
Acknowledgements
This work was supported by NIH grant #HL38223 and New Jersey Agricultural Experiment Station Hatch grant #14146. The authors wish to thank Drs. Susan K. Fried, Malcolm Watford, and Judith Storch for their insightful advice.
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Current address: Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855, USA.