Walnut oil increases cholesterol efflux through inhibition of stearoyl CoA desaturase 1 in THP-1 macrophage-derived foam cells

January 1, 2011 Human Health and Nutrition Data 0 Comments

Walnut oil increases cholesterol efflux through inhibition of stearoyl CoA desaturase 1 in THP-1 macrophage-derived foam cells

Year: 2011
Authors: Zhang, J. Grieger, J.A. Kris-Etherton, P.M. Thompson, J.T. Gillies, P.J. Fleming, J.A. Vanden Heuvel, J.P.
Publication Name: Nutrition & Metabolism
Publication Details: Volume 8; Pages 61 – 73.

Abstract:

Walnuts significantly decrease total and low-density lipoprotein cholesterol in normo- and hypercholesterolemic individuals. No study to date has evaluated the effects of walnuts on cholesterol  efflux, the initial step in reverse cholesterol transport, in macrophage-derived foam cells (MDFC). The present study was conducted to investigate the mechanisms by which walnut oil affects cholesterol efflux.  Methods: The extract of English walnuts (walnut oil) was dissolved in DMSO and applied to cultured THP-1 MDFC cells (0.5 mg/mL). THP-1 MDFC also were treated with human sera (10%, v:v) taken from subjects in a walnut feeding study. Cholesterol efflux was examined by liquid scintillation counting. Changes in gene expression were quantified by real time PCR. Results: Walnut oil treatment significantly increased cholesterol efflux through decreasing the expression of the lipogenic enzyme stearoyl CoA desaturase 1 (SCD1) in MDFC. Alpha-linolenic acid (ALA), the major n-3 polyunsaturated fatty acids found in walnuts, recaptured SCD1 reduction in MDFC, a mechanism mediated through activation of nuclear receptor farnesoid-X-receptor (FXR). Postprandial serum treatment also increased cholesterol efflux in MDFC. When categorized by baseline C-reactive protein (CRP; cut point of 2 mg/L), subjects in the lower CRP sub-group benefited more from dietary intervention, including a more increase in cholesterol efflux, a greater reduction in SCD1, and a blunted postprandial lipemia. Conclusion: In conclusion, walnut oil contains bioactive molecules that significantly improve cholesterol efflux in MDFC. However, the beneficial effects of walnut intake may be reduced by the presence of a pro-inflammatory state ((Authors abstract).
Walnuts contain high levels of PUFA, both linoleic acid (LA) and alpha-linolenic acid (ALA), the latter is also high in flax. A hypocholesterolemic effect of walnuts is attributed to decreased de novo lipogenesis due to their high PUFA content. However, no study to date has evaluated the effects of walnuts on cholesterol efflux. RCT begins with cholesterol export across the cytoplasm membrane, a process known as cholesterol efflux. A previous study showed that the ALA significantly decreases cholesterol storage and increases cholesterol efflux in macrophage-derived foam cells by inhibiting the lipogenic enzyme, stearoyl CoA desaturase1 (SCD1) through activation of a nuclear receptor farnesoid-X-receptor (FXR) pathway. SCD1 is an endoplasmic reticulum enzyme that converts saturated fatty acids, palmitic acid and stearic acid, to MUFAs (palmitoleic acid and oleic acid). Due to its critical role in hepatic de novo lipogenesis, SCD1 has been proposed as a new drug target for obesity and metabolic syndrome. Manipulation of SCD1 impacts cholesterol efflux but it is not clear whether SCD1 could be a drug or dietary target to prevent atherosclerosis progression. In the present study, the hypothesis that PUFAs, especially n-3 PUFA ALA rich walnut oil would favorably affect cholesterol efflux and SCD1 expression in THP-1 MDFC was tested. Following walnut oil treatment (0.5 mg/mL), cholesterol efflux was significantly increased by 35%, compared to DMSO control treatment. Among the key enzymes tested in the lipid synthesis (FAS, ACC, HMGCR, ELOVL6) and oxidation (CPT, ACO) pathways, only SCD1 mRNA was significantly reduced in a dose-dependent manner following walnut oil treatment. Walnut oil treatment significantly increased ligand-dependent activation of human FXR, LXR and PXR, whereas minimal effects were seen for PPARa, b/δ, g and RXRa. Walnut oil and its predominant n3 PUFA ALA significantly increased FXR mRNA expression. The in vitro data suggests that walnut oil and the n-3 PUFA ALA increases cholesterol efflux in foam cells. Among the n3 PUFAs evaluated, ALA was significantly increased by 3-fold (197%) after the consumption of walnut oil.  Study participants were overweight with a mean BMI of 29.7 kg/m2 (BMI = 30 kg/m2 being obese). Serum CRP from participants who consumed walnut oil ranged through 0.29 mg/L to 17.3 mg/L, with a median of 1.9 mg/L at baseline. However, participants in the high CRP sub-group had a significantly higher (36%) postprandial TG response (calculated as area under the curve, AUC), compared with participants in the low CRP sub-group. Following walnut oil intake, postprandial sera (collected at 4 h) from the low CRP subgroup significantly reduced SCD1 protein level by 30%, compared with that of high CRP sub-group. The findings suggest that the inhibition of SCD1 by ALA plays a critical role in increasing the level of cholesterol efflux. In this study, sera from subjects consuming walnuts decreased SCD1 expression and increased cholesterol efflux. A higher CRP level is a marker of a pro-inflammatory state and is highly correlated with increased risks of metabolic syndrome and cardiovascular diseases. Results from several studies demonstrated that an elevated inflammatory state impairs cholesterol efflux and increase SCD1 activity. In the present study, although SCD1 mRNA was slightly decreased by serum from the high CRP sub-group, this did not translate into any significant improvement in efflux presumably due to the higher levels of circulating inflammatory mediators. The studies presented demonstrated that ALA rich walnut oil significantly reduced SCD1 expression as well as increased cholesterol efflux in macrophage derived foam cells, which will be of benefit for atherosclerosis regression. These same results would be expected for ALA rich flaxseed and oil (Editors comments).



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