Lysophospholipid Acylation Modulates Plasma Membrane Lipid Organization and Insulin Sensitivity in Skeletal Muscle

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2021 Feb 16

PMID 33591957

Citations 24

Authors

Patrick J Ferrara

Xin Rong

J Alan Maschek

Anthony Rp 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

Affiliations

Soon will be listed here.

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.

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