Role of MAPKp38 in liver steatosis

Background and aims:

Obesity is a major health problem associated with many other diseases like type two diabetes T2DM, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). In fact, NAFLD is one of the most prevalent manifestations of obesity and this chronic liver disease has become a worldwide health problem. In these diseases are described an increase of intracellular p38 mitogen-activated protein kinase (MAPK) signaling, which may promote tissue inflammation and injury. The family members of p38 MAPK are proteins that regulate different and important process like proliferation and apoptosis. These kinases are activated for a double phosporilation on serine and threonine for MKK3 and MKK6. There are four p38MAK isoform with different roles in the signaling, p38alpha,beta ,gamma and delta While p38alpha and beta are the most well known, p38gamma and p38delta still less understood. In fact, the p38alpha has been implicated in the development of insulin resistance and p38delta in the production and release of insulin and in the development of obesity induced pancreatitis. In the other hand, MKK3, the upstream kinase was described that has an important role of declining renal function in diabetic mice, while the other upstream kinase, MKK6 inhibited IRS-1 and IRS-2 expressions in adipocytes.

The objective of our study is to investigate the role of p38gamma/delta in the control of liver steatosis using genetic modified mice and human samples.

Our results indicate that p38gamma/delta play a important role in the development of steatosis due to the control of inflammation and cytokine release. Lack of p38gamma/delta in myeloid cell causes a reduction of steatosis, liver necrosis and oxidative stress after methionine choline deficient diet.

These results indicate that p38gamma/delta could be a possible target for the treatment of hepatic steatosis.