De Novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation

Xiaochao Wei, Jochen G. Schneider, Sherene M. Shenouda, Ada Lee, Dwight A. Towler, Manu V. Chakravarthy, Joseph A. Vita, Clay F. Semenkovich

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease.

Original languageEnglish (US)
Pages (from-to)2933-2945
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number4
DOIs
StatePublished - Jan 28 2011

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Lipoylation
Fatty Acid Synthases
Lipogenesis
Nitric Oxide Synthase Type III
Blood Vessels
Homeostasis
Insulin
Endothelial cells
Medical problems
Endothelial Cells
Multifunctional Enzymes
Diabetic Angiopathies
Palmitates
Capillary Permeability
Diabetes Complications
Cell membranes
Hindlimb
Nutritional Status
Biological Availability
Leukocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

De Novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation. / Wei, Xiaochao; Schneider, Jochen G.; Shenouda, Sherene M.; Lee, Ada; Towler, Dwight A.; Chakravarthy, Manu V.; Vita, Joseph A.; Semenkovich, Clay F.

In: Journal of Biological Chemistry, Vol. 286, No. 4, 28.01.2011, p. 2933-2945.

Research output: Contribution to journalArticle

Wei, X, Schneider, JG, Shenouda, SM, Lee, A, Towler, DA, Chakravarthy, MV, Vita, JA & Semenkovich, CF 2011, 'De Novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation', Journal of Biological Chemistry, vol. 286, no. 4, pp. 2933-2945. https://doi.org/10.1074/jbc.M110.193037
Wei, Xiaochao ; Schneider, Jochen G. ; Shenouda, Sherene M. ; Lee, Ada ; Towler, Dwight A. ; Chakravarthy, Manu V. ; Vita, Joseph A. ; Semenkovich, Clay F. / De Novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 4. pp. 2933-2945.
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