Liver and systemic insulin resistance
Authors: Nicolas Lanthier, Isabelle A. Leclercq
Journal: Hepatology (2014)

The burden of nonalcoholic fatty liver is related to the risk for nonalcoholic steatohepatitis (NASH) and progressive fibrosis, but also to extrahepatic higher morbidity and mortality rates. Hepatic insulin resistance (IR), the hallmark of fatty liver, irrespectively of disease stage, could represent an ideal culprit because it may influence both local liver fibrosis and systemic complications.1 In a recent issue of Hepatology, Yang et al.'s progress in our understanding of mechanisms for liver inflammation and fibrosis reveals the implication of hepatocyte transforming growth factor beta (TGF-β) signaling in NASH pathogenesis. Using a choline-deficient L-amino-acid (CDAA) defined diet to induce steatohepatitis in albumin-Cre/TGF-β receptor 2 (TGFβR2)flox/flox mice, they show that abrogation of TGFβR2-mediated signaling in hepatocytes protected mice from hepatic injury, fibrosis, and hepatocyte death. This pleiotropic cytokine, besides its known role in fibrogenesis, also directly acts on hepatocytes to induce steatosis, cell damage, and inflammation, the indispensable features of NASH.2 Interestingly, they observed that alteration of hepatocyte TGFβR2-mediated signaling had peripheral effects outside the liver. CDAA-hepatocyte TGFβR2−/− mice presented a lower body weight, a better glucose tolerance, and a higher insulin sensitivity, compared to CDAA-fed wild-type mice, suggesting that hepatocyte TGF-β signaling and/or ensuing hepatocyte injury and liver inflammation affect whole-body insulin sensitivity. However, the data presented by the researchers appear insufficient to draw such a conclusion. Feeding mice a CDAA diet causes hepatic injury and perturbation in lipid metabolism with increased liver triglyceride storage and circulating free fatty acids.2 However, it is not known to alter glucose homeostasis. As reported by the same group elsewhere, the homeostasis model assessment of IR index was similar in CDAA and control CSAA-fed animals,3 questioning IR in the model and the physiological consequence of modification of insulin sensitivity and glucose tolerance observed upon hepatocyte-specific deletion TGFβR2. Dynamic tests for insulin sensitivity and glucose tolerance were used in the study, with concomitant insulinemia not being reported. The researchers interpreted decreased glucose tolerance as resulting from systemic IR, which implicates decreased glucose uptake by peripheral tissues. However, local hepatic IR (i.e., unrefrained hepatic glucose output) could also yield a similar glucose curve during the glucose tolerance test. Therefore, evaluation of the activation of the signaling cascade in response to insulin in skeletal muscle and adipose tissue as well as in the liver, and/or a hyperinsulinemic-euglycemic clamp study, the gold standard to evaluate in vivo insulin sensitivity and glucose fluxes, would be most appropriate to assess the compartments (hepatic versus peripheral) in which insulin sensitivity is altered upon hepatic TGFβR2 disruption. If validated, the observation by Yang et al. will add to previous experimental observation4, 5 and provide further support to the operation of a liver-to-peripheral tissue signaling loop modulating metabolism and insulin sensitivity. Finally, the researchers suggest that TGF-β-Smad signaling may influence systemic or adipose tissue inflammation that, in turn, will negatively affect systemic insulin sensitivity. Here, again, evaluation of adipose tissue inflammation in the model and upon TGFβR2 deletion would be needed to provide support to this attractive hypothesis. This elegant study provides new data regarding the mechanistic implication of TGF-β signaling in inducing steatohepatitis-like lesions. At this stage, we believe that data remain insufficient to support the proposition that hepatic TGFβR2-mediated signaling also regulates peripheral metabolic features and systemic insulin sensitivity. Nicolas Lanthier, M.D., Ph.D. Isabelle A. Leclercq, M.D., Ph.D. Laboratory of Hepatogastroenterology Institut de Recherche Expérimentale et Clinique Université Catholique de Louvain Brussels, Belgium