title: Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance.
abstract: The liver extracellular matrix (ECM) expands with high-fat (HF) feeding. This finding led us to address whether receptors for the ECM, integrins, are key to the development of diet-induced hepatic insulin resistance. Integrin-linked kinase (ILK) is a downstream integrin signaling molecule involved in multiple hepatic processes, including those related to differentiation, wound healing, and metabolism. We tested the hypothesis that deletion of ILK in mice on an HF diet would disrupt the ECM-integrin signaling axis, thereby preventing the transformation into the insulin-resistant liver. To determine the role of ILK in hepatic insulin action in vivo, male C57BL/6J ILKlox/loxmice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILKlox/loxAlbcre). Results from this study show that hepatic ILK deletion has no effect on insulin action in lean mice but sensitizes the liver to insulin during the challenge of HF feeding. This effect corresponds to changes in the expression and activation of key insulin signaling pathways as well as a greater capacity for hepatic mitochondrial glucose oxidation. This demonstrates that ILK contributes to hepatic insulin resistance and highlights the previously undefined role of integrin signaling in the pathogenesis of diet-induced hepatic insulin resistance.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN ashley.s.williams@duke.edu.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Elijah
authors.initials: E
authors.lastname: Trefts
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.|Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.affiliation: Department of Anesthesiology, Vanderbilt University, Nashville, TN.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Grueter
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.|Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN.|Department of Medicine, Veteran Affairs, Nashville, TN.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN.|Department of Medicine, Veteran Affairs, Nashville, TN.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.|Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005109:Extracellular Matrix / Q000378:metabolism*; D017353:Gene Deletion; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D014280:Triglycerides; D000099200:Scaffold Protein ILK