Integrin Linked Kinase is Critical for Hepatic Cellular Organization, Metabolism, and Glucoregulation

Abstract

The current obesity public health crisis is linked directly with liver health through a parallel epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD has direct effects on liver health while acting as an independent risk factor for type II diabetes, chronic heart disease, and chronic kidney disease. NAFLD is rooted in the metabolic consequences of overnutrition. As such, understanding hepatic metabolism and its many control systems serves to better define the origin of these diseases while leading to novel therapies. Alterations to extracellular matrix (ECM) composition and integrin signaling systems have now been implicated in the progression of metabolic pathologies including hepatic insulin resistance and NAFLD. This work focuses on newly appreciated metabolic regulation by the ECM-integrin signaling system as a means to understand metabolic disease of the liver. This body of work expands the current understanding of integrin involvement in metabolic processes in vivo through the lens of integrin-linked kinase (ILK). Results of this work demonstrate pathologic contributions of this protein during obesity and the spectrum of benefits that occur when this protein is removed from hepatocytes. This work also establishes the underlying mechanisms whereby removal of ILK from hepatocytes elicits these benefits. To conclude, this work establishes the hepatic metabolic functions mediated by ILK in order to expand understanding of novel pathways and targets in the progression of pathologic understanding and treatment.