Scopus Publication Detail
The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in Scopus. This abstract is what is used to create the fingerprint of the publication.
Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilisation and glucose transport dysfunction in skeletal muscle
K.M. Habegger; B.A. Penque; W. Sealls; L. Tackett; L.N. Bell; E.K. Blue; P.J. Gallagher; M. Sturek; M.A. Alloosh; H.O. Steinberg; et al. (Profiled Authors: Mouhamad Alloosh; Jeffrey S. Elmendorf; Patricia J. Gallagher; Michael S. Sturek; Robert V. Considine)
Aims/hypothesis: Diminished cortical filamentous actin (F-actin) has been implicated in skeletal muscle insulin resistance, yet the mechanism(s) is unknown. Here we tested the hypothesis that changes in membrane cholesterol could be a causative factor, as organised F-actin structure emanates from cholesterol-enriched raft microdomains at the plasma membrane. Methods: Skeletal muscle samples from high-fat-fed animals and insulin-sensitive and insulin-resistant human participants were evaluated. The study also used L6 myotubes to directly determine the impact of fatty acids (FAs) on membrane/cytoskeletal variables and insulin action. Results: High-fat-fed insulin-resistant animals displayed elevated levels of membrane cholesterol and reduced F-actin structure compared with normal chow-fed animals. Moreover, human muscle biopsies revealed an inverse correlation between membrane cholesterol and whole-body glucose disposal. Palmitate-induced insulin-resistant myotubes displayed membrane cholesterol accrual and F-actin loss. Cholesterol lowering protected against the palmitate-induced defects, whereas characteristically measured defects in insulin signalling were not corrected. Conversely, cholesterol loading of L6 myotube membranes provoked a palmitate-like cytoskeletal/GLUT4 derangement. Mechanistically, we observed a palmitate-induced increase in O-linked glycosylation, an end-product of the hexosamine biosynthesis pathway (HBP). Consistent with HBP activity affecting the transcription of various genes, we observed an increase in Hmgcr, a gene that encodes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. In line with increased HBP activity transcriptionally provoking a membrane cholesterol-based insulin-resistant state, HBP inhibition attenuated Hmgcr expression and prevented membrane cholesterol accrual, F-actin loss and GLUT4/glucose transport dysfunction. Conclusions/interpretation: Our results suggest a novel cholesterolgenic-based mechanism of FA-induced membrane/cytoskeletal disorder and insulin resistance. © 2011 The Author(s).
PMID: 22002007 PMCID: PMC3245823
This section shows information related to the publication - computed using the fingerprint of the publication - including related publications, related experts with fingerprints representing significant amounts of overlap between their fingerprint and this publication. The red dots indicate whether those experts or terms appear within the publication, thereby showing potential and actual connections.
Jayme D. Allen; Zahara M. Jaffer; Su-Jung Park; Sarah Burgin; Clemens Hofmann; Mary Ann Sells; Shi Chen; Ethel Derr-Yellin; Elizabeth G. Michels; Andrew McDaniel; et al.Blood. 2009;113(12):2695-2705.
Joseph T. Brozinick Jr.; Eric D. Hawkins; Andrew B. Strawbridge; Jeffrey S. ElmendorfJournal of Biological Chemistry. 2004;279(39):40699-40706.
Alicia M. McCarthy; Kristen O. Spisak; Joseph T. Brozinick; Jeffrey S. ElmendorfAmerican Journal of Physiology - Cell Physiology. 2006;291(5):C860-C868.
Appears in this Document