In the CDAA model, mice develop steatosis in the absence of a high fat diet, mice continue to eat, do not reduce the appetite and the amount of calories introduced and weight changes are similar to control diet. Furthermore, in comparison to other existing rodent models, CDAA is able to drive the progression of steatosis toward a condition of inflammation and fibrosis. We have investigated the potential mechanisms that could Lorazepam explain the hepatic steatosis. First of all we demonstrated that CDAA-treated mice were more insulin resistant already at one month as compared to the control CSAA diettreated mice. Data in the literature show controversial results concerning the potential condition of insulin resistance in the course of CDAA treatment in rodents, mainly based on methods that provide only a partial and indirect measurement of insulin resistance, and related to the fasting glycemic and insulinemic state. Here insulin resistance was measured by the euglycemic-hyperinsulinemic clamp, which represents the gold standard for the evaluation of insulin sensitivity, and the results were confirmed by finding increased fasting insulin concentrations. This condition was even NDT 9513727 enhanced by the addition of CCl4 to the diet. The mechanisms by which CDAA diet induces insulin resistance are unknown but could be related to the gut microbiota metabolism of choline as shown in humans. Metabolomics data have indicated that reduced concentrations of lysophosphocholine, in particular reduced lyso-PC C18:2, and lyso-PC C16:0, are associated with peripheral insulin resistance and hepatic steatosis. Moreover, we found that CDAA diet increases Inflammasome components in the liver, which supports our hypothesis of a possible link between gut microbiota modifications, insulin resistance and progression of liver injury. The discovery that CDAA diet induces peripheral insulin resistance is important for the translation of this animal model to the human studies. To our knowledge, this is the first experimental model where a clear link between peripheral insulin resistance, NASH development and HCC formation has been established. In human patients with NAFLD/NASH, peripheral insulin resistance is a primary feature of the disease, even in lean subjects that do not present the characteristics of metabolic syndrome. Moreover, a worse peripheral insulin resistance state has been associated with the presence of fibrosis.