• Williams AS, Trefts E, Lantier L, Grueter CA, Bracy DP, James FD, Pozzi A, Zent R, Wasserman DH. Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance. Diabetes. 2017 Feb;66(2). 325-334. PMID: 27899483 [PubMed]. PMCID: PMC5248997.

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 ILK(lox/lox) mice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILK(lox/lox)Albcre). 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.