Role of hepatic p38δ MAPK in liver metabolism

Resumen

Hepatic metabolism is a complex regulatory network which controls whole body homeostasis. Therefore, it is crucial to deeply understand its function, to better comprehend human physiology and to find novel targets and effective clinical approaches to treat metabolic diseases that are reaching pandemic proportions such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Contrary to the role of c-Jun NH2-terminal kinases (JNK) in hepatocytes, the role of the p38 mitogen-activated protein kinases (MAPK), other stress kinases, and among them, the role of the p38δ MAPK isoform in hepatocytes is unknown. Interestingly, since the expression of this kinase is increased in livers from obese patients with NAFLD, p38δ might play a main function in liver metabolism. Therefore, the main purpose of this thesis was to clarify the function of the hepatic p38δ MAPK in liver metabolism, its repercussion in whole body homeostasis and its function in obesity, to open new avenues for this kinase as a putative target in obesity-related T2D and NAFLD. We demonstrated that p38δ MAPK is a key regulator of glucose metabolism and it is essential to keep normoglycemia. Particularly, p38δ MAPK controls glycogen metabolism and glycolysis, through phosphorylation of glycogen synthase 2 (GYS2) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) respectively. We showed that mice lacking p38δ in hepatocytes presented decreased glycogenesis, hepatic glycogen storage and consequently, reduced blood glucose levels. This protected against hyperglycemia in high fat diet (HFD)-fed mice and promoted mild hypoglycemia in chow diet (CD)-fed mice. Moreover, HFD-fed mice lacking p38δ in hepatocytes showed reduced glycolysis, which may impair the hepatic de novo lipogenesis (DNL), the subsequent intrahepatic lipid accumulation and therefore, protect against NAFLD and insulin resistance development. Additionally, p38δ MAPK may also control lipid metabolism, regulating PPARα pathway and FGF21 plasma levels. Moreover, it might have an important role controlling different lipid oxidation pathways. Lastly, p38δ might also have a main function in the hepatic metabolism of long-chain acyl CoA (LCCoA) and diacylglycerides (DAG). Summarizing, this Thesis work firstly defines the function of the hepatic p38δ MAPK, identifying substrates for this kinase; giving therefore new insights into the complex stress kinases network. Secondly, this thesis reveals that p38δ MAPK is a central metabolic regulator, mainly controlling glucose but also lipid metabolism. Lastly, p38δ MAPK might be a target to treat T2D and NAFLD, because not only the lack of p38δ MAPK in hepatocytes, but also the downregulation of the hepatic p38δ in obese mice; protect against hyperglycemia, insulin resistance and NAFLD. Summary