Universität zu Köln

Stoffel, Wilhelm, Binczek, Erika, Schmidt-Soltau, Inga, Brodesser, Susanne and Wegner, Ina (2021). High fat / high cholesterol diet does not provoke atherosclerosis in the omega 3-and omega 6-polyunsaturated fatty acid synthesis-inactivated Delta 6-fatty acid desaturase-deficient mouse. Mol. Metab., 54. AMSTERDAM: ELSEVIER. ISSN 2212-8778

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Abstract

Objective: An increased w6/w3-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 w3-and w6-PUFAs in the pathogenesis of dyslipoproteinemia and atherosclerosis has been a topic of intense efforts for several decades. Cellular homeostasis of the w3-and w6-PUFA pool is maintained by the synthesis of w3-and w6-PUFAs from essential fatty acids (EFA) (linoleic and a-linolenic acid) and their dietary supply. In this study, we used the auxotrophic A6-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 w3-and w6-PUFAs (Western diet) in the pathogenesis of multifactorial dyslipoproteinemia and atherosclerosis. We focused on the metabolic axisdliver 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. Methods: 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. Results: w3-and w6-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. d) 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. Conclusions: Deficiency of w3-and w6-PUFA in the fads2-/-mutant perturbs liver lipid metabolism, causes hypocholesterolemia and hypotriglyceridemia and renders the fads2-/-mutant resistant to sustained atherogenic HFHC diet. Neither PUFA-free regular nor long-term HFHC-diet impacts the apoe- and LDL-receptor deficiencyeprovoked hypercholesterolemia and atherosclerotic plaque formation, size and distribution in the aorta. Our study strongly suggests that the absence of PUFAs as highly vulnerable chemical targets of autoxidation attenuates inflammatory responses and the formation of atherosclerotic lesions. 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 a lifespan, pivotal for legitimate dietary recommendations. (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stoffel, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Binczek, Erika UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt-Soltau, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wegner, Ina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-566884
DOI:	10.1016/j.molmet.2021.101335
Journal or Publication Title:	Mol. Metab.
Volume:	54
Date:	2021
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	2212-8778
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RAB GTPASES; GENE; ACTIVATION; MECHANISMS; ALPHA Multiple languages Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/56688