Sphingolipids at the Crossroads of NAFLD and Senescence

Nonalcoholic fatty liver disease (NAFLD) is a group of liver disorders encompassing simple hepatic steatosis and its more aggressive forms of nonalcoholic steatohepatitis and cirrhosis. It is a rapidly growing health concern and the major cause for the increasing incidence of primary liver tumors. Unequivocal evidence shows that sphingolipid metabolism is altered in the course of the disease and these changes might contribute to NAFLD progression. Recent data provide solid support to the notion that deregulated ceramide and sphingosine-1-phosphate metabolism are present at all stages of NAFLD, i.e., steatosis, nonalcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma (HCC). Insulin sensitivity, de novo lipogenesis, and the resulting lipotoxicity, fibrosis, and angiogenesis are all seemingly regulated in a manner that involves either ceramide and/or sphingosine-1-phosphate. Sphingolipids might also participate in the onset of hepatocellular senescence. The latter has been shown to contribute to the advancement of cirrhosis to HCC in the classical cases of end-stage liver disease, i.e., viral- or alcohol-induced; however, emerging evidence suggests that senescence is also involved in the pathogenicity of NAFLD possibly via changes in ceramide metabolism.