Neutral Sphingomyelinase-2 (nSMase-2) is an enzyme that catalyzes the turnover of sphingomyelin and governs one of the several metabolic pathways to make bioactive ceramide. nSMase-2 plays a role in cellular response to inflammatory cytokines, oxidative stress, tumor development, osteogenesis, to name a few. In the liver, nSMase-2 is expressed at very low level; however, it becomes upregulated in some liver pathologies, including Non Alcoholic Fatty Liver Disease (NAFLD), the hepatic manifestation of metabolic syndrome. Understanding the biological functions of nSMase-2 in NAFLD is of particular interest since de-regulated ceramide metabolism is one of the key characteristics of the functional decline of multiple organs in the course of the disease.
When treated with free fatty acids, HepG2 cell form lipid droplets and exhibit insulin resistance. In response to excess supply with palmitate, but not oleate, nSMase-2 is increasingly palmitoylated and translocates from intracellular organelles to the plasma membrane. This is associated with elevated ceramide production and is causatively linked to suppression of insulin signaling. In vivo studies in mice carrying a liver specific deletion of nSMase-2 and their respective wild type controls support such role of nSMase-2 in the onset of hepatic insulin resistance. Our experiments also indicate that in mice with diet-induced steatosis, a significant portion of nSMase-2 localizes to the mitochondrial fraction and may be associated with a specific subpopulation of mitochondria that regulates lipid droplet size and TAG content.
Thus, our experiments identify nSMase-2 as a novel addition to the sphingolipid-centric concept of NAFLD and, more broadly, metabolic syndrome. It seems plausible that nSMase-2 activation during NAFLD is mechanistically linked to that of SPT and even sphingosine kinases, and that sphingolipid metabolic network(s) might be an essential part of the mechanism of this complex disease.