Volume 47, Issue 1, Pages 142-156 (July 2007) Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences  Isabelle A. Leclercq, Alain Da Silva Morais, Ben Schroyen, Noémi Van Hul, Albert Geerts  Journal of Hepatology  Volume 47, Issue 1, Pages 142-156 (July 2007) DOI: 10.1016/j.jhep.2007.04.002 Copyright © 2007 European Association for the Study of the Liver Terms and Conditions

Fig. 1 (a) Insulin regulates glucose homeostasis and maintains normoglycaemia. Insulin favours glucose uptake by adipocytes and skeletal muscles and, by controlling glucose synthesis and storage, inhibits hepatic glucose output. In addition, insulin inhibits the activity of hormone-sensitive lipoprotein lipase, and thereby stimulates lipid storage in the adipose tissue. (b) In the insulin resistant state, decreased insulin sensitivity results in decreased glucose uptake by the peripheral tissues and decreased inhibition of hepatic glucose output. This concurs to hyperglycaemia and compensatory hyperinsulinaemia. The inhibition of lipoprotein lipase is reduced, leading to increased lipid storage in non-adipose tissues such as the liver and the muscles. This has significant consequences on insulin signaling in those tissues. In addition, the balance of adipocytokines is altered in fat-laden and insulin resistant adipose tissue impinging on insulin sensitivity. Journal of Hepatology 2007 47, 142-156DOI: (10.1016/j.jhep.2007.04.002) Copyright © 2007 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Schematic representation of intracellular insulin signaling. Upon insulin binding, the cytoplasmic kinase domain of the activated insulin receptor (IR) trans-phosphorylates several tyrosine residues, acting as docking sites for downstream interacting proteins. Insulin receptor interacting proteins (including insulin receptor substrates (IRS) 1–6, Shc, Cbl, p62dok, or Gab-1) are in turn phosphorylated, activating three main pathways: (1) the phosphatidylinositol-3-kinase (PI3K) pathway is mainly involved in the control of metabolic actions by insulin (glucose, lipid and protein metabolism), transcription of GLUT4, protein synthesis (via mTOR) and control of cell survival, (2) the mitogen-activated protein kinase (MAPK) pathway which mediates the mitogenic, growth and cell differentiation effects, and (3) signal transduction through the CAP/Cbl/Tc10 pathway which controls the membrane translocation of glucose transporter GLUT4, in GLUT4-expressing cells. Journal of Hepatology 2007 47, 142-156DOI: (10.1016/j.jhep.2007.04.002) Copyright © 2007 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Regulation of SREBP-1c. The transcription factor sterol regulatory element-binding protein (SREBP-1c) mediates most of insulin’s effects on lipogenesis. The precursor is retained into the endoplasmic reticulum and can be freed in times of sterol depletion. Free SREBP-1c translocates to the Golgi where it is cleaved by specific proteases: the released N-terminal fragment migrates to the nucleus and activates transcription of genes implicated in lipogenesis [19]. In addition, its level of phosphorylation modulates SREBP-1c activity. Sterol depletion and TNF regulate, in an insulin-independent way, the maturation and activity of SREBP-1c. Insulin regulates the maturation, the activity as well as the transcription of SREBP-1c and Insig2a. The latter participates in the retention of SREBP-1c in the endoplasmic reticulum. Journal of Hepatology 2007 47, 142-156DOI: (10.1016/j.jhep.2007.04.002) Copyright © 2007 European Association for the Study of the Liver Terms and Conditions

Fig. 4 Intrahepatic insulin resistance: possible interactions between sinusoidal cells and hepatocytes. Hyperglycaemia, hyperinsulinaemia, increased free fatty acids (FFA) and increased intracellular fatty acids, reactive oxygen species (ROS) and advanced glycation end-products (AGEs), altered balance of adipocytokines and the low-grade inflammation, all concur and participate in intrahepatic insulin resistance. Those factors are able to alter the biology of sinusoidal cells, in ways that are only partially understood. Whether those factors also induce insulin resistance in sinusoidal cells, and in the affirmative, whether signaling modifications alter the biology of those cells have been poorly explored. Sinusoidal cells produce reactive oxygen species (ROS) and a large array of bioactive peptides. Whether those are implicated, via paracrine stimulations, in hepatic insulin resistance remains to be investigated. KC, Kupffer cells; HSC, hepatic stellate cells; SEC, sinusoidal endothelial cells. Journal of Hepatology 2007 47, 142-156DOI: (10.1016/j.jhep.2007.04.002) Copyright © 2007 European Association for the Study of the Liver Terms and Conditions