Combined Therapy of Dietary Fish Oil and Stearoyl-CoA Desaturase 1 Inhibition Prevents the Metabolic Syndrome and Atherosclerosis

Abstract

Background-Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of energy metabolism and inflammation. We have previously reported that inhibition of SCD1 in hyperlipidemic mice fed a saturated fatty acid (SFA)-enriched diet prevented development of the metabolic syndrome, yet surprisingly promoted severe atherosclerosis. In this study we tested whether dietary fish oil supplementation could prevent the accelerated atherosclerosis caused by SCD1 inhibition. Methods and Results-LDLr, ApoB 100/100 mice were fed diets enriched in saturated fat or fish oil in conjunction with antisense oligonucleotide (ASO) treatment to inhibit SCD1. As previously reported, in SFA-fed mice, SCD1 inhibition dramatically protected against development of the metabolic syndrome, yet promoted atherosclerosis. In contrast, in mice fed fish oil, SCD1 inhibition did not result in augmented macrophage inflammatory response or severe atherosclerosis. In fact, the combined therapy of dietary fish oil and SCD1 ASO treatment effectively prevented both the metabolic syndrome and atherosclerosis. Conclusions-SCD1

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

“…These paradoxical results have been largely ignored due to the overwhelming success of the SCD1-KO models in preventing obesity. However, recent work has shown clearly that despite its ability to prevent obesity, loss of SCD1 is associated with an increased risk for atherogenesis in SCD1 Ϫ / Ϫ × LDLR Ϫ / Ϫ double-knockout animals ( 46,47 ). Furthermore, our previous work looking at skin-specifi c deletion of SCD1 (SKO) ( 18 ) indicates that increased energy expenditure accounts for the anti-obesity effect and that increased ␤ -oxidation likely prevents accumulation of toxic DAG and SFA.…”

Molecular Basis of Insulin Resistance and Its Relation to Metabolic Syndrome

“…Glitazones and metformin have been used increasingly over the recent years for the management of insulin resistance. The ongoing search for new strategies to combat the MetS has shed light on new molecules that may prove to be effective therapeutic targets in treating the syndrome; in vivo studies have established that atherosclerosis driven by the inhibition of stearoyl-coenzyme A desaturase 1 (SCD1), an enzyme involved in fatty acid metabolism, can be completely prevented by the omega-3 polyunsaturated fatty acids in dietary fish-oils [52] . Moreover, our data showing that in some patients, high doses of omega-3 polyunsaturated fatty acids will normalize the 2-hour post-prandial glucose levels in a sample from Puerto Rico is promising.…”

Importância da relação dos ácidos graxos omega-6/omega-3 na alimentação

“…Desde essa observação, os efeitos benéficos dos acidos graxos poli-insaturados principalmente da família n-3 têm se estendido a benefícios relacionados a níveis de lipídios séricos, ação antitrombocitária sobre as plaquetas e proteção contra algumas doenças como o câncer, doença inflamatória intestinal e artrite reumatóide (SIMOPOULOS, 2008a;2008b;ERKKILA et al, 2008;CHUNG;SAWYER, 2010).…”

“…As LDL no homem são responsáveis pelo transporte da maior parte de colesterol sérico. Humanos que receberam dietas ricas em ácidos graxos n-3, apresentaram LDL diminuída no plasma, ocorrendo também um aumento das lipoproteínas de alta densidade (HDL), estão desejáveis, já que são responsáveis pelo trasporte reverso do colesterol, onde é feito o transporte dos tecidos periféricos para o fígado (SIMOUPOULOS, 2006;CHUNG;SAWYER, 2010).…”

“…Oposto a isso, ocorre o aumento do colesterol das lipoproteínas de alta densidade (HDL), estas que são desejáveis, por serem responsáveis pelo transporte de colesterol dos tecidos periféricos para o fígado, conhecido como transporte reverso do colesterol (SIMOPOULOS, 2006;CHUNG;SAWYER., 2010).…”