Long-lasting impact of perinatal dietary supplementation of omega 3 fatty acids on mevalonate pathway: potential role on neuron trophism in male offspring hippocampal formation

ABSTRACT

Objective: We were aimed at evaluating the long-term impact of perinatal an omega-3 fatty acid-enriched diet on the mevalonate/cholesterol pathway in the brain of male offspring.

Methods: Female rats were fed with standard or omega-3 fatty acid-enriched diet during pregnancy and lactation. Liver, brain and plasma were collected from infant, adolescent and adult male offspring for subsequent biochemical and morphological analyses.

Results: The omega-3 enriched diet induced region-dependent changes of the 3-hydroxy 3-methylglutaryl Coenzyme A reductase in the brain and affected notably RhoA/CREB signaling and the nerve growth factor content in the hippocampus. Our data reveal a long-lasting impact of perinatal omega-3 fatty acid supplementation on hippocampal nerve growth factor levels mediated by reduced 3-hydroxy 3-methylglutaryl Coenzyme A reductase activation state and enhanced CREB signaling.

Discussion: These data underline the importance of the perinatal omega-3 enriched diet for adult brain function and reveal a new pathway important for nerve growth factor regulation.

KEYWORDS:

• Cholesterol
• hydroxy-methylglutaryl Coenzyme A reductase
• mevalonate pathway
• nerve growth factor
• omega 3 fatty acids

Acknowledgements

The Authors are in debt with dr. Frank W. Pfrieger, INCI, CRNS University of Strasbourg, France for the invaluable suggestions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Datasets are available from the corresponding author on reasonable request.

Additional information

Funding

This research was funded by PRIN-MIUR, Contract grant number: 2015SHM58M_004 to VP - Departments of Excellence - 2017 - legge 232/2016 - art.1, commi 314–337 awarded to Dept. of Science - University Roma Tre - Rome - Italy for 2018–2022; Ministero dell’Istruzione, dell’Università e della Ricerca.

Notes on contributors

Claudia Tonini

Claudia Tonini: [email protected]; Claudia Tonini obtained her Master Degree summa cum laude in Biology applied to Molecular, Cellular and Pathophysiological Research at University of Roma Tre. Starting from November 2017, she is PhD student in Biomedical Science and Technologies (Curriculum Physiologu)at the University of Roma Tre. Her research interest is focused on the effects of perinatal exposition to diet- and environmental-derived molecules on cholesterol metabolism/dys-metabolism, and its pathophysiological implications.

Sara Schiavi

Sara Schiavi: [email protected]; Sara Schiavi obtained her Master Degree summa cum laude in Biology applied to Molecular, Cellular and Pathophysiological Research at University of Roma Tre. Starting from November 2016, she is PhD student in Biomedical Science and Technologies (Curriculum of Pharmacology) at the University of Roma Tre. Her research interest is focused on the Role of the endocannabinoid system in preclinical models of neurodevelopmental disorders.

Fabrizio Macca

Fabrizio Macca: [email protected]; Fabrizio Macca obtained his Master Degree summa cum laude in Biology applied to Molecular, Cellular and Pathophysiological Research at University of Roma Tre March 2019. His Master thesis was focused on the omega-3 effects on cholesterol metabolism.

Marco Segatto

Marco Segatto: [email protected]; Marco Segatto developed a great interest in cholesterol homeostasis since his Master degree thesis, focusing the attention on the physiopathological role played by lipid homeostasis in different organs such as skeletal muscle and brain. He continued to acquire new skills and knowledge about cholesterol metabolism in the brain as a PhD student and as a post-Doc fellow. Currently, he is working as tenured assistant professor at University of Molise, and his interests are still focused on the involvement of lipid metabolism in brain and muscle physiopathology.

Viviana Trezza

Viviana Trezza: [email protected]; Viviana Trezza graduated cum laude from the University of Rome ‘Sapienza’ in 2003. In the same University, she got her PhD in Pharmacology and Toxicology in 2007. From 2005 till 2010, she worked as Researcher at the Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands. In 2010, she has been appointed Assistant Professor at the Department of Science, Roma Tre University, Rome, Italy, where she set up her own laboratory. In 2008, Viviana Trezza has been appointed Associate Professor of Pharmacology at the Department of Science of Roma Tre University, where she is currently Head of pharmacology Laboratory. Her research interests are focused on the involvement of endocannabinoid system in emotions and cognitions.

Valentina Pallottini

Valentina Pallottini got a Master Degree in Biological Science, University Sapienza, Rome, a Master in Neurobiology, University Sapienza, Rome, a PhD in Health and life science: biology of organisms and physiology, University of Strasbourg, France. She was researcher in Dompé Farmaceutici S.p.A, L'Aquila, Italy, Laboratory Assistant at the Department of Biology, University Roma Tre, Assistant Professor in Physiology, Dept. Sciences, University Roma Tre and since 2014: Associate Professor in Physiology Dept. Sciences, University Roma Tre, Rome. Her research has been principally focused on HMG-CoA reductase (the rate limiting enzyme of cholesterol biosynthetic pathway) regulation and on cholesterol metabolism in different physiological states. During the last years, she has been focused on cholesterol metabolism and dys-metabolism in Central Nervous System and possible associations with neurodevelopmental and neurodegenerative disorders.