Integrin‐Linked Kinase is Necessary for Normal Hepatic Glycogen Storage and Energy Metabolism

Abstract

A recently established characteristic of obesity and its associated insulin resistance is altered extracellular matrix (ECM) in a broad range of tissues, including adipose tissue, skeletal muscle, heart, kidney and liver. This results in increased ECM and abnormal morphology. The cell is informed of the state of the ECM by interaction of ECM with integrin receptors. In recent years the contribution of these receptors to the development of insulin resistance has been realized using a high fat fed mouse model of diet-induced obesity (DIO). Integrin receptor signaling occurs through a number of distinct intracellular signaling nodes. Among the critical hubs of integrin signaling is integrin-linked kinase (ILK). Hepatocyte-specific knockout of ILK (hILK-KO) is beneficial in models of hepatic damage, regeneration, and insulin resistance. It has also been reported that hILK causes age-dependent effects on hepatic gene expression and signaling. It remains to be determined whether the age-dependence of hepatic gene expression is associated with distinct metabolic responses during times of metabolic stress. Thus, it was the initial aim of these studies to determine glucose tolerance and body composition of hILK-KO mice during the growth phase of the mouse as specific hepatic genes are deficient. We hypothesized beneficial effects of hILK-KO on glucose tolerance in young mice (6-wk old). This hypothesis was confirmed as hILK-KO mice presented with improved glucose tolerance relative to wild type (WT) mice at 6-weeks of age. We further investigated the underlying metabolic drivers of altered glucose homeostasis in these mice. Despite lower glucose concentrations after a 5-hour fast, gluconeogenic processes are accelerated in 6-week old hILK-KO mice. Decreased hepatic glycogen content coincides with lower 5 h fasting glucose and improved glucose tolerance. Impaired glycogen synthesis also occurs in these mice during a refeeding challenge. This occurs despite intact insulin-stimulated glycogen synthesis signaling. hILK-KO livers also possess decreased energy in the adenine nucleotide pool during metabolic flux analyses. Hepatocytes isolated from hILK-KO livers also have lower respiration metrics on a per cell basis, but increased mitochondrial content indicated by VDAC protein levels. These attributes are also accompanied by decreased Bnip3 and increased p62 protein levels indicating impaired autophagy/mitophagy. In summary we demonstrate that hILK-KO leads to an impaired energy buffering system in hepatocytes, possibly through deficient autophagy. Studies in hepatocytes suggest that this accelerates glycolysis as an energy-producing process, which limits the availability of glucose for glycogenesis. This inability to store glycogen also accelerates fasting transitions and increases reliance on gluconeogenesis to buffer circulating glucose, which compounds energy demand of hepatocytes. Therefore, ILK is required for establishment of normal energy and glucose metabolism in the liver of mice in the growth phase. This indicates ILK as a potential intermediary signal for integrin-mediated effects on metabolism in hepatic physiology. Support or Funding Information DK050277, DK007563, DK112553, DK059637 Graphical summary of the metabolic effects of hepatocyte specific knockout of integrin-linked kinase. Abbreviations: ILK- integrin-linked kinase; ATP- adenosine triphosphate; GS- glycogen synthase. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.