EPA and DHA differentially modulate membrane elasticity in the presence of cholesterol

Miranda L. Jacobs; Hammad A. Faizi; Justin A. Peruzzi; Petia M. Vlahovska; Neha P. Kamat

doi:10.1016/j.bpj.2021.04.009

EPA and DHA differentially modulate membrane elasticity in the presence of cholesterol

Miranda L. Jacobs, Hammad A. Faizi, Justin A. Peruzzi, Petia M. Vlahovska, Neha P. Kamat^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Polyunsaturated fatty acids (PUFAs) modify the activity of a wide range of membrane proteins and are increasingly hypothesized to modulate protein activity by indirectly altering membrane physical properties. Among the various physical properties affected by PUFAs, the membrane area expansion modulus (K_a), which measures membrane strain in response to applied force, is expected to be a significant controller of channel activity. Yet, the impact of PUFAs on membrane K_a has not been measured previously. Through a series of micropipette aspiration studies, we measured the apparent K_a (K_app) of phospholipid model membranes containing nonesterified fatty acids. First, we measured membrane K_app as a function of the location of the unsaturated bonds and degree of unsaturation in the incorporated fatty acids and found that K_app generally decreases in the presence of fatty acids with three or more unsaturated bonds. Next, we assessed how select ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), affect the K_app of membranes containing cholesterol. In vesicles prepared with high amounts of cholesterol, which should increase the propensity of the membrane to phase segregate, we found that inclusion of DHA decreases the K_app in comparison to EPA. We also measured how these ω-3 PUFAs affect membrane fluidity and bending rigidity to determine how membrane K_app changes in relation to these other physical properties. Our study shows that PUFAs generally decrease the K_app of membranes and that EPA and DHA have differential effects on K_app when membranes contain higher levels of cholesterol. Our results suggest membrane phase behavior and the distribution of membrane-elasticizing amphiphiles impact the ability of a membrane to stretch.

Original language	English (US)
Pages (from-to)	2317-2329
Number of pages	13
Journal	Biophysical Journal
Volume	120
Issue number	11
DOIs	https://doi.org/10.1016/j.bpj.2021.04.009
State	Published - Jun 1 2021

Funding

This work was supported by the Air Force Office of Scientific Research YIP FA9550-19-1-0039 P00001 to N.P.K., the Searle Funds at The Chicago Community Trust , and a National Science Foundation (NSF) grant MCB-1935356 (N.P.K.). M.L.J. was supported by Grant No. T32GM008382 from the National Institute of General Medical Sciences and The American Heart Association Predoctoral Fellowship under Grant No. 20PRE35180215 . J.A.P. was supported by the NSF Graduate Research Fellowship and the Ryan Fellowship and International Institute for Nanotechnology at Northwestern University . P.M.V. and H.A.F. were supported by NSF grant CMMI-1748049 . This work made use of IMSERC at Northwestern University. IMSERC has received support from the Soft and Hybrid Nanotechnology Experimental Resource ( NSF ECCS-1542205 ), the State of Illinois , and the International Institute for Nanotechnology . Wayne State Lipidomics Core Facility is supported in part by National Center for Research Resources, National Institutes of Health Grant S10RR027926 . We thank Prof. Robert Raphael for his experimental advice, helpful discussions, and careful reading of the manuscript. We also thank members of the Kamat Lab for thoughtful discussions. This work was supported by the Air Force Office of Scientific Research YIP FA9550-19-1-0039 P00001 to N.P.K. the Searle Funds at The Chicago Community Trust, and a National Science Foundation (NSF) grant MCB-1935356 (N.P.K.). M.L.J. was supported by Grant No. T32GM008382 from the National Institute of General Medical Sciences and The American Heart Association Predoctoral Fellowship under Grant No. 20PRE35180215. J.A.P. was supported by the NSF Graduate Research Fellowship and the Ryan Fellowship and International Institute for Nanotechnology at Northwestern University. P.M.V. and H.A.F. were supported by NSF grant CMMI-1748049. This work made use of IMSERC at Northwestern University. IMSERC has received support from the Soft and Hybrid Nanotechnology Experimental Resource (NSF ECCS-1542205), the State of Illinois, and the International Institute for Nanotechnology. Wayne State Lipidomics Core Facility is supported in part by National Center for Research Resources, National Institutes of Health Grant S10RR027926.

ASJC Scopus subject areas

Biophysics

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10.1016/j.bpj.2021.04.009

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title = "EPA and DHA differentially modulate membrane elasticity in the presence of cholesterol",

abstract = "Polyunsaturated fatty acids (PUFAs) modify the activity of a wide range of membrane proteins and are increasingly hypothesized to modulate protein activity by indirectly altering membrane physical properties. Among the various physical properties affected by PUFAs, the membrane area expansion modulus (Ka), which measures membrane strain in response to applied force, is expected to be a significant controller of channel activity. Yet, the impact of PUFAs on membrane Ka has not been measured previously. Through a series of micropipette aspiration studies, we measured the apparent Ka (Kapp) of phospholipid model membranes containing nonesterified fatty acids. First, we measured membrane Kapp as a function of the location of the unsaturated bonds and degree of unsaturation in the incorporated fatty acids and found that Kapp generally decreases in the presence of fatty acids with three or more unsaturated bonds. Next, we assessed how select ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), affect the Kapp of membranes containing cholesterol. In vesicles prepared with high amounts of cholesterol, which should increase the propensity of the membrane to phase segregate, we found that inclusion of DHA decreases the Kapp in comparison to EPA. We also measured how these ω-3 PUFAs affect membrane fluidity and bending rigidity to determine how membrane Kapp changes in relation to these other physical properties. Our study shows that PUFAs generally decrease the Kapp of membranes and that EPA and DHA have differential effects on Kapp when membranes contain higher levels of cholesterol. Our results suggest membrane phase behavior and the distribution of membrane-elasticizing amphiphiles impact the ability of a membrane to stretch.",

author = "Jacobs, {Miranda L.} and Faizi, {Hammad A.} and Peruzzi, {Justin A.} and Vlahovska, {Petia M.} and Kamat, {Neha P.}",

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AU - Jacobs, Miranda L.

AU - Faizi, Hammad A.

AU - Peruzzi, Justin A.

AU - Vlahovska, Petia M.

AU - Kamat, Neha P.

PY - 2021/6/1

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N2 - Polyunsaturated fatty acids (PUFAs) modify the activity of a wide range of membrane proteins and are increasingly hypothesized to modulate protein activity by indirectly altering membrane physical properties. Among the various physical properties affected by PUFAs, the membrane area expansion modulus (Ka), which measures membrane strain in response to applied force, is expected to be a significant controller of channel activity. Yet, the impact of PUFAs on membrane Ka has not been measured previously. Through a series of micropipette aspiration studies, we measured the apparent Ka (Kapp) of phospholipid model membranes containing nonesterified fatty acids. First, we measured membrane Kapp as a function of the location of the unsaturated bonds and degree of unsaturation in the incorporated fatty acids and found that Kapp generally decreases in the presence of fatty acids with three or more unsaturated bonds. Next, we assessed how select ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), affect the Kapp of membranes containing cholesterol. In vesicles prepared with high amounts of cholesterol, which should increase the propensity of the membrane to phase segregate, we found that inclusion of DHA decreases the Kapp in comparison to EPA. We also measured how these ω-3 PUFAs affect membrane fluidity and bending rigidity to determine how membrane Kapp changes in relation to these other physical properties. Our study shows that PUFAs generally decrease the Kapp of membranes and that EPA and DHA have differential effects on Kapp when membranes contain higher levels of cholesterol. Our results suggest membrane phase behavior and the distribution of membrane-elasticizing amphiphiles impact the ability of a membrane to stretch.

AB - Polyunsaturated fatty acids (PUFAs) modify the activity of a wide range of membrane proteins and are increasingly hypothesized to modulate protein activity by indirectly altering membrane physical properties. Among the various physical properties affected by PUFAs, the membrane area expansion modulus (Ka), which measures membrane strain in response to applied force, is expected to be a significant controller of channel activity. Yet, the impact of PUFAs on membrane Ka has not been measured previously. Through a series of micropipette aspiration studies, we measured the apparent Ka (Kapp) of phospholipid model membranes containing nonesterified fatty acids. First, we measured membrane Kapp as a function of the location of the unsaturated bonds and degree of unsaturation in the incorporated fatty acids and found that Kapp generally decreases in the presence of fatty acids with three or more unsaturated bonds. Next, we assessed how select ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), affect the Kapp of membranes containing cholesterol. In vesicles prepared with high amounts of cholesterol, which should increase the propensity of the membrane to phase segregate, we found that inclusion of DHA decreases the Kapp in comparison to EPA. We also measured how these ω-3 PUFAs affect membrane fluidity and bending rigidity to determine how membrane Kapp changes in relation to these other physical properties. Our study shows that PUFAs generally decrease the Kapp of membranes and that EPA and DHA have differential effects on Kapp when membranes contain higher levels of cholesterol. Our results suggest membrane phase behavior and the distribution of membrane-elasticizing amphiphiles impact the ability of a membrane to stretch.

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EPA and DHA differentially modulate membrane elasticity in the presence of cholesterol

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