Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle
Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai
Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai
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Research Article Metabolism Muscle biology

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Abstract

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle–specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle–specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Authors

Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James E. Cox, Saame Raza Shaikh, Peter Tontonoz, William L. Holland, Katsuhiko Funai

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Figure 10

Disruption of caveolae is sufficient to normalize insulin signaling with LPCAT3 knockdown.

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Disruption of caveolae is sufficient to normalize insulin signaling with...
C2C12 myoblasts were infected with lentivirus expressing shRNA for scrambled (SC) or LPCAT3-knockdown (KD) sequences and were differentiated into myotubes. (A–D) Myotubes were incubated with or without 10 mM of methyl-β-cyclodextrin (MβCD) for 1 hour. (A and B) MβCD successfully depletes cav3 (P < 0.001, main effect of LPCAT3 knockdown) but not flotillin-1 (P = 0.003, main effect of LPCAT3 knockdown; P = 0.01, main effect of MβCD) (n = 9). (C and D) Cells were incubated in the presence (0.6 nM) or absence of insulin and were blotted for total or Ser473 phosphorylation of Akt (n = 3 basal, n = 6 insulin). (E and F) C2C12 myotubes were incubated in the absence or presence of either PDGF (2.5 ng/mL), EGF (100 ng/mL), or insulin (12 nM) and were blotted for total or Ser473 phosphorylation of Akt (basal and insulin, n = 8; PDGF and EGF, n = 10). Two-way ANOVA with Šidák’s multiple-comparison test was performed. All data are represented as mean ± SEM. *P ≤ 0.05.