Implicating Cellular Senescence in the Fibrosis and Inflammation of NASH
Nonalcoholic steatohepatitis, NASH, is a condition characterized by chronic inflammation and fibrosis in the liver. Fibrosis is a malfunction of tissue maintenance, the deposition of excessive, scar-like collagen that disrupts tissue structure and function. Like all fibrotic diseases, means of effectively reversing the progression of NASH are presently lacking. NASH is a lifestyle condition, a consequence of fatty liver and obesity, but losing weight and otherwise changing lifestyle will not significantly reverse established fibrosis and loss of liver function. Where fibrosis and inflammation characterize a condition, we might by now expect senescent cells to be involved. Senescent cells secrete pro-growth, pro-inflammatory signals, and there is good evidence for cellular senescence to drive the progression of fibrosis in many tissues, including kidney, heart, and lungs. Thus why not the liver as well?
Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines with the senescence-inducing drugs nutlin-3a, doxorubicin, and etoposide. The senescence-associated markers p16, p21, p53, and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis.
Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of insulin receptor, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.