Role of Hepatic p38delta MAPK in Liver Metabolism

Abstract

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 uncover 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 particularly, the role of the p38δ MAPK isoform in hepatocytes is unknown. Interestingly, the expression of p38δ MAPK is increased in livers from obese patients with NAFLD, suggesting that this kinase might play an important 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 obesityrelated T2D and NAFLD. We demonstrated that p38δ is a key regulator of glucose metabolism and it is essential to keep normoglycemia. Particularly, we found that p38δ 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 (Albp38δKO) presented decreased glycogenesis, hepatic glycogen storage and consequently, reduced blood glucose levels. This protected against high fat diet (HFD)induced hyperglycemia and promoted mild hypoglycemia in chow diet (CD)-fed mice. Moreover, HFD-fed Albp38δKO mice 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 might control lipid metabolism, regulating peroxisome-proliferator-activated receptor α (PPARα) pathway and hepatokine fibroblast growth factor 21 (FGF21) plasma levels. Moreover, p38δ might regulate different lipid oxidation pathways. Lastly, p38δ might also have a main function in the hepatic metabolism of long-chain acyl CoAs (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 the lack of p38δ MAPK in hepatocytes protects against hyperglycemia, insulin resistance and NAFLD.