Essential fatty acids (EFA) linoleic and alpha-linolenic acid and derived long-chain (LC) and very long-chain omega-3-and omega-6-polyunsaturated fatty acids (PUFAs) are pivotal structural elements in the architecture of all mammalian membrane systems and precursors of structurally and functionally diverse signaling molecules operative in pathways regulating lipid and energy metabolism. Homeostasis of the cellular pool of ω3- and ω6- PUFAs is maintained by dietary supply and the transformation of EFAs to long chain - and very long chain ω3- and ω6-PUFAs in an orchestrated sequence at the tetrameric chain-elongation and trimeric desaturase complex in the endoplasmic reticulum, the dominant site of PUFA synthesis.
An increased ω6/ω3-polyunsaturated fatty acid in the current Western diet is regarded as a critical epigenetic nutritional factor in the pathogenesis of several human life style diseases, metabolic syndrome, cardiovascular disease, the central nervous system and the female and male 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.
In this study, Wilhelm Stoffel and his collaborators 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. Their study was focused on the metabolic axis: liver endoplasmic reticulum (ER), serum lipoprotein system (Lp) and aorta vessel wall.
Furthermore, they 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.
In their experimental set-up cohorts f +/+ and fads2-/- mice underwent the two following 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, the fads2-/- x apoe-/- and the fads2-/- xldlr-/- double knockout mutants were generated.
"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 lipid droplets and serum-lipoprotein proﬁles and cellular reactions in the aortic wall", Wilhelm Stoffel comments. Data show, that ω3-and ω6-PUFA synthesis deﬁciency in the fads2-/- mouse causes a) hypocholesterolemia and hypotriglyceridemia, b) dyslipoproteinemia with a shift of high-density lipoprotein (HDL) to very low-density lipoprotein (VLDL)-enriched Lp-pattern and c) altered liver lipid droplet structures. Furthermore, long-term HFHC diet does not trigger atherosclerotic plaque formation in the aortic arc, the thoracic and abdominal aorta of PUFA-deﬁcient fads2-/- mice. Inactivation of the fads2-/- locus, abolishing systemic PUFA synthesis in the fads2-/- x apoe-/- and fads2-/- x ldlr-/- double knockout mouse lines.
The results of these studies combining the unbiased genetic model and stringent feeding conditions, unveiled molecular links between the suppression of omega-3-and omega-6-PUFA synthesis and prolonged PUFA-free regular and high fat/high cholesterol diets, perturbed membrane lipidomes and lipid metabolism of liver, lipid droplets and lipoproteins. They led to the surprising observation that suppression of PUFA-synthesis in the fads2-/- mouse on neither PUFA-free regular diet nor prolonged PUFA-free HFHC (“Western”) diet triggered atherosclerotic plaque formation in the aortic arc, the thoracic and abdominal aorta. In addition, immuno-histochemical observations strongly suggest the deleterious role of PUFAs as highly vulnerable chemical targets of autoxidation, releasing reactive aldehydes (e.g., HNE (4-hydroxynonenal) and covalently modifying proteins to novel autoantigens, which trigger inﬂammatory responses in atherosclerotic lesions.
"Our study demonstrates the necessity of a scrutinized view of the pleiotropic functions of omega-3-and omega-6-PUFAs as molecular culprits or benefactors during the lifespan, before they are included in legitimate dietary recommendations. The cumulative data and insight into the molecular basis of the pleiotropic functions of PUFAs challenge a differentiated view of PUFAs as culprits or benefactors during the lifespan, pivotal for legitimate dietary recommendations", Wilhelm Stoffel says.
The study was published in Molecular Metabolismus DOI: 10.1016/j.molmet.2021.101335
Prof. Dr. Dr. Dr. h.c. Wilhelm Stoffel
Laboratory of Molecular Neuroscience, Institute of Biochemistry
SRG at the Center for Molecular Medicine Cologne
Faculty of Medicine, University of Cologne
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
Wilhlem Stoffel1,2,3, Erika Binczek2, Inga Schmidt-Soltau2 , Susanne Brodesser3 and Ina Wegner2
1,2Laboratory of Molecular Neuroscience, Institute of Biochemistry, University of Cologne, 2 Center for Molecular Medicine (CMMC), Faculty of Medicine, and 3 Cluster of Excellence, Cellular Stress Response in Aging-Related Diseases (CECAD), University of Cologne, DE.