Role of new lipids FAHFAs in the brain and their involvement in pathological conditions.
Endocrinology, Diabetology, Metabolism
Cell Biology
Final Report Abstract
A new class of endogenous lipids consisting of a fatty-acid bound to a hydroxy-fatty acid was discovered by Dr. Barbara Kahn’s laboratory. A subfamily of these lipids, the Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) exerts anti-diabetic and anti-inflammatory actions. In this project we aimed to analyze the potential protective role of PAHSAs in brain inflammation. We firstly address brain inflamamtion in a mouse model of high fat diet feeding. Due to mild changes in brain inflammation and neurogenic markers induced by acute and chronic high-fat diet, we only observed a modest PAHSA-mediated protective effect. Therefore we moved to another model associated to elevated brain inflammation, the Alzheimer’s disease (AD). We used an in vitro 3D model of human derived neural cells. This model is the ReNcell VM cell line, which are neural stem cells that can give rise to neurons and astrocytes. This cell line is engineered to express human APP (Aβ precursor protein) and PSEN1 (presenilin1) transgenes containing a total of five AD-linked mutations in these two genes. Specific PAHSA isomers tended to decrease different forms of amyloid Aβ produced by these cells. By using the naive ReNcell VM cell line lacking AD mutations in a pro-inflammatory model of IL1β supplementation (which plays a detrimental role in Alhzeimers disease), we observed a protective role of PAHSAs. These lipids were able to reduce the IL1β-induced secretion of MCP1, IL8, SerpinE1. Taken together, our data suggest that PAHSAs exert partial protective effects in two models of brain inflammation, i.e. high-fat diet and AD, although only the latest was associated to high proinflammatory conditions.
Publications
- Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation? Mol Cell Endocrinol. 2017 Feb 5;441:156-163
Steenblock C, Rubin de Celis MF, Androutsellis-Theotokis A, Sue M, Delgadillo Silva LF, Eisenhofer G, Andoniadou CL, Bornstein SR
(See online at https://doi.org/10.1016/j.mce.2016.09.011) - Isolation and characterization of adrenocortical progenitors involved in the adaptation to stress. Proc Natl Acad Sci USA. 2018 Dec 18;115(51):12997-13002
Steenblock C, Rubin de Celis MF, Delgadillo Silva LF, Pawolski V, Brennand A, Werdermann M, Berger I, Santambrogio A, Peitzsch M, Andoniadou CL, Schally AV, Bornstein SR
(See online at https://doi.org/10.1073/pnas.1814072115) - PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice. J Clin Invest. 2019 Aug 5;129:3717-3731
Syed I, Rubin de Celis MF, Mohan JF, Moraes-Vieira PM, Vijayakumar A, Nelson AT, Siegel D, Saghatelian A, Mathis D, Kahn BB
(See online at https://doi.org/10.1172/JCI122445)
