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

被引：47

作者：

Ferrara, Patrick J. ^{[1
,2
,3
,4
,5
]}

Rong, Xin ^{[6
]}

Maschek, J. Alan ^{[1
,7
]}

Verkerke, Anthony Rp ^{[1
,2
,3
,4
]}

Siripoksup, Piyarat ^{[1
,8
]}

Song, Haowei ^{[9
]}

Green, Thomas D. ^{[3
]}

Krishnan, Karthickeyan C. ^{[10
]}

Johnson, Jordan M. ^{[1
,2
,3
,4
]}

Turk, John ^{[9
]}

Houmard, Joseph A. ^{[3
,4
]}

Lusis, Aldons J. ^{[10
]}

Drummond, Micah J. ^{[1
,5
,8
]}

McClung, Joseph M. ^{[3
]}

Cox, James E. ^{[1
,7
,11
]}

Shaikh, Saame Raza ^{[3
,12
]}

Tontonoz, Peter ^{[6
]}

Holland, William L. ^{[1
,2
,5
]}

Funai, Katsuhiko ^{[1
,2
,3
,4
,5
,8
]}

机构：

[1] Univ Utah, Diabet & Metab Res Ctr, Salt Lake City, UT USA

[2] Univ Utah, Dept Nutr & Integrat Physiol, Salt Lake City, UT USA

[3] East Carolina Univ, East Carolina Diabet & Obes Inst, Greenville, NC USA

[4] East Carolina Univ, Human Performance Lab, Greenville, NC 27858 USA

[5] Univ Utah, Mol Med Program, Salt Lake City, UT USA

[6] UCLA, Dept Pathol & Lab Med, Los Angeles, CA USA

[7] Univ Utah, Metabol Mass Spectrometry Prote Core, Salt Lake City, UT USA

[8] Univ Utah, Dept Phys Therapy & Athlet Training, Salt Lake City, UT USA

[9] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO USA

[10] UCLA, Dept Med, Cardiol Div, Los Angeles, CA 90024 USA

[11] Univ Utah, Dept Biochem, Salt Lake City, UT USA

[12] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27515 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 08期

关键词：

SATURATED FATTY-ACIDS; GLUCOSE-METABOLISM; ARACHIDONIC-ACID; PROTEIN-KINASE; MICE SHOW; RESISTANCE; ACYLTRANSFERASE; RECEPTOR; DIACYLGLYCEROL; CELLS;

D O I：

10.1172/JCI135963

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16

共 79 条

[1] Ceramide content is increased in skeletal muscle from obese insulin-resistant humans [J].