High fat / high cholesterol diet does not provoke atherosclerosis in the ω3-and ω6-polyunsaturated fatty acid synthesis–inactivated Δ6-fatty acid desaturase–deficient mouse

• Published in: Molecular metabolism (Germany) 2021-12, Vol.54, p.101335-101335, Article 101335
• Main Authors: Stoffel, Wilhelm, Binczek, Erika, Schmidt-Soltau, Inga, Brodesser, Susanne, Wegner, Ina
• Format: Article
• Language: English
• Subjects: Animals; Atherogenic nutrition; Atherosclerosis - metabolism; Atherosclerotic lesions; Cholesterol, Dietary - adverse effects; Diet, High-Fat - adverse effects; Dyslipoproteinemia; Fatty Acid Desaturases - deficiency; Fatty Acid Desaturases - genetics; Fatty Acid Desaturases - metabolism; Fatty Acids, Omega-3 - biosynthesis; Fatty Acids, Omega-6 - biosynthesis; Hepatic lipid metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Original; PUFA synthesis deficiency; Receptors, LDL - deficiency; Receptors, LDL - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2021.101335

An increased ω6/ω3-polyunsaturated fatty acid ratio in the current Western diet is regarded as a critical epigenetic nutritional factor in the pathogenesis of several human lifestyle diseases, metabolic syndrome, cardiovascular disease, the central nervous system and the female and male reproductive systems. The impact of nutrient ω3-and ω6-PUFAs in the pathogenesis of dyslipoproteinemia and atherosclerosis has been a topic of intense efforts for several decades. Cellular homeostasis of the ω3-and ω6- PUFA pool is maintained by the synthesis of ω3-and ω6-PUFAs from essential fatty acids (EFA) (linoleic and α-linolenic acid) and their dietary supply. In this study, we used the auxotrophic Δ6-fatty acid desaturase- (FADS2) deficient mouse (fads2−/−), an unbiased model congenial for stringent feeding experiments, to investigate the molecular basis of the proposed protective role of dietary ω3-and ω6-PUFAs (Western diet) in the pathogenesis of multifactorial dyslipoproteinemia and atherosclerosis. We focused on the metabolic axis—liver endoplasmic reticulum (ER), serum lipoprotein system (Lp) and aorta vessel wall. Furthermore, we addressed the impact of the inactivated fads2-locus with inactivated PUFA synthesis on the development and progression of extended atherosclerosis in two different mouse mutants with disrupted cholesterol homeostasis, using the apoe−/− and ldlr−/− mutants and the fads2−/− x apoe−/− and fads2−/− x ldlr−/− double mutants. Cohorts of +/+ and fads2−/− mice underwent two long-term dietary regimens: a) a PUFA-free standard chow diet containing only EFAs, essential for viability, and b) a high fat/high cholesterol (HFHC) diet, a mimicry of the human atherogenic “Western” diet. c) To study the molecular impact of PUFA synthesis deficiency on the development and progression of atherosclerosis in the hypercholesterolemic apoe−/− and ldlr−/− mouse models fed PUFA-free regular and sustained HFHC diets, we generated the fads2−/− x apoe−/− and the fads2−/− x ldlr−/− double knockout mutants. We assessed essential molecular, biochemical and cell biological links between the diet-induced modified lipidomes of the membrane systems of the endoplasmic reticulum/Golgi complex, the site of lipid synthesis, the PL monolayer and neutral lipid core of LD and serum-Lp profiles and cellular reactions in the aortic wall. ω3-and ω6-PUFA synthesis deficiency in the fads2−/− mouse causes a) hypocholesterolemia and hypotriglyceridemia, b) dyslipoproteinemia with a