Role of Ceramidase in Regulating Hepatic Lipid Metabolism and Whole Body Insulin Sensitivity

Concomitant with the rise in obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD), a newly emerging obesity-related disorder, has also been rising steadily. NAFLD is a chronic liver disease that ranges histologically from simple steatosis in its mildest form to non-alcoholic steatohepatitis (NASH) in the more severe form, which is characterized by hepatocyte inflammation and fibrosis. In recent years, sphingolipids have garnered increasing attention for their role in the development of diabetes and metabolic syndrome. Specifically, the accumulation of ceramides in liver was shown to be associated with both hepatic insulin resistance and NAFLD. We recently demonstrated that the adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2. The associated ceramidase activity promotes ceramide degradation and generation of sphingosine 1-phosphate (S1P). To further investigate the tissue-specific effects of the receptor associated ceramidase activity, we have developed transgenic mice that inducibly express adiponectin receptors 1 and 2 under the control of a tetracycline response element. Hepatic overexpression of adiponectin receptors improved whole body glucose metabolism and prevented hepatic steatosis. Furthermore, we found that catabolism of hepatic ceramides improved insulin signaling in the adipocyte, which suggests the existence of a "cross-talk" between liver and adipose tissue.