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 8

Generation and characterization of mice with skeletal muscle–specific overexpression of LPCAT3 (LPCAT3-MKI).

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Generation and characterization of mice with skeletal muscle–specific ov...
(A) Schematic of mouse conditional LPCAT3 knockin (LPCAT3cKI+/+) with insertion of mouse LPCAT3 cDNA sequence in the Rosa26 locus preceded by a stop codon flanked with loxP sites. (B) Genotyping of LPCAT3cKI+/+ mice crossed with HSA-MCM+/– mice to generate LPCAT3cKI+/–; HSA-MCM–/– (Ctrl) or LPCAT3cKI+/–; HSA-MCM+/– (LPCAT3-MKI) mice. (C) Quantitative RT-PCR of LPCAT3 in tibialis anterior (TA) (Ctrl n = 9, MKI n = 17), soleus (Ctrl n = 5, MKI n = 5), heart (Ctrl n = 3, MKI n = 4), and liver (Ctrl n = 4, MKI n = 4). (D–I) Lipids were extracted from TA muscles and quantified for lyso-PC (D), PC (E), and lyso-PC/PC ratio (F) (Ctrl n = 7, MKI n = 12). (G) Body mass of Ctrl and LPCAT3-MKI mice fed a standard chow diet or after 12 weeks of HFD feeding. (H and I) Intraperitoneal glucose tolerance test (H) and AUC (I) from glucose tolerance test between Ctrl and LPCAT3-MKI mice after HFD feeding (Ctrl n = 4, MKI n = 3). Two-tailed t tests (C–G and I) or 2-way ANOVA (H) was performed. All data are represented as mean ± SEM. *P ≤ 0.05.