Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?  Claire Z. Larter, Geoffrey C. Farrell  Journal of Hepatology  Volume 44, Issue 2, Pages 253-261 (February 2006) DOI: 10.1016/j.jhep.2005.11.030 Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Causes of hepatic insulin resistance. Obesity induces sub-acute inflammation that promotes insulin resistance by increasing hepatic SOCS expression (via IL-6). SOCS inhibits insulin signalling directly by competing for phosphorylation sites on the insulin receptor, and indirectly by inducing SREBP-1c. In turn, SREBP-1c suppresses IRS2 synthesis, and increases fatty acid synthesis. Hepatic levels of fatty acyl-CoA increase in response to serum NEFA (fatty acids arriving from peripheral lipolysis), dietary intake and endogenous fatty acid synthesis, or from impaired β-oxidation (possibly the result of mitochondrial injury). This increase in fatty acyl-CoA (and possibly other lipid metabolites) activates PKC-θ to catalyse serine/threonine phosphorylation of the IRS proteins, and/or IKK-β to activate NF-κB with release of IL-6 and augmentation of SOCS induction. [This figure appears in colour on the web.] Journal of Hepatology 2006 44, 253-261DOI: (10.1016/j.jhep.2005.11.030) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Hepatic lipid homeostasis. Lipid homeostasis is achieved by balancing fatty acid synthesis with fatty acid oxidation and export. Fatty acid synthesis is induced by insulin and glucose via the transcription factors SREBP-1c and ChREBP, respectively. LXR also promotes fatty acid synthesis by inducing SREBP-1c. Fatty acid oxidation is promoted by PPAR-α and the protein kinase, AMPK. Adiponectin, an adipocytokine, increases hepatic fatty acid oxidation by inducing PPAR-α and AMPK; increased levels of hepatic fatty acids also induce PPAR-α. PPAR-α and LXR have opposite functions but their engagement of the same heteropartner, RXR, enables hepatocytes to transiently commit to either fatty acid synthesis or fatty acid oxidation. [This figure appears in colour on the web.] Journal of Hepatology 2006 44, 253-261DOI: (10.1016/j.jhep.2005.11.030) Copyright © 2005 European Association for the Study of the Liver Terms and Conditions