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 4

Administration of CI-976 in vitro and in vivo.

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Administration of CI-976 in vitro and in vivo. (A–D) C2C12 myoblasts wer...
(A–D) C2C12 myoblasts were differentiated into myotubes with either CI-976 or vehicle. (A and B) Quantification of MC540 fluorescence (n = 6). (C and D) Western blot and quantification of Thr308 phosphorylation and total Akt in the presence (12 nM) and absence of insulin (n = 14; P = 0.024, main effect of insulin). (E–G) WT C57BL6/J mice were fed with HFD for 6 weeks, with subcutaneous injection for the last 7 days with vehicle (1:9 ethanol/polyethylene glycol) or 30 mg/kg CI-976. Body mass (E), intraperitoneal glucose tolerance excursion curves (F), and AUC (G) from glucose tolerance tests on vehicle-treated or CI-976–injected mice (n = 8 per group). Two-tailed t tests (B, E, and G) or 2-way ANOVA with Šidák’s multiple-comparison test (D and F) was performed. All data are represented as mean ± SEM. *P ≤ 0.05.