title: Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action.
abstract: Increased cholesterol efflux from macrophage-derived foam cells (MDFCs) is an important protective mechanism to decrease lipid load in the atherosclerotic plaque. Dietary alpha-linolenic acid (ALA), an omega-3 polyunsaturated fatty acid (PUFA), decreases circulating cholesterol, but its role in cholesterol efflux has not been extensively studied. Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids (MUFAs). Endogenous MUFAs are preferentially incorporated into triglycerides, phospholipids and cholesteryl ester, which are abundant in atherosclerotic plaque. This study investigated the mechanisms by which ALA regulated SCD1 and subsequent effect on cholesterol storage and transport in MDFCs. Small interfering RNA (siRNA) also was applied to modify SCD1 expression in foam cells. Alpha-linolenic acid treatment and SCD1 siRNA significantly decreased SCD1 expression in MDFCs. The reduction of SCD1 was accompanied with increased cholesterol efflux and decreased intracellular cholesterol storage within these cells. Alpha-linolenic acid activated the nuclear receptor farnesoid-X-receptor, which in turn increased its target gene small heterodimer partner (SHP) expression, and decreased liver-X-receptor dependent sterol regulatory element binding protein 1c transcription, ultimately resulting in repressed SCD1 expression. In conclusion, repression of SCD1 by ALA favorably increased cholesterol efflux and decreased cholesterol accumulation in foam cells. This may be one mechanism by which dietary omega-3 PUFAs promote atherosclerosis regression.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Penny M
authors.initials: PM
authors.lastname: Kris-Etherton
authors.forename: Jerry T
authors.initials: JT
authors.lastname: Thompson
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hannon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gillies
authors.forename: John P Vanden
authors.initials: JP
authors.lastname: Heuvel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D017962:alpha-Linolenic Acid / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D005229:Fatty Acids, Monounsaturated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D017962:alpha-Linolenic Acid; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse