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Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1β gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1β gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1β and hepatic lipogenesis. [ABSTRACT FROM AUTHOR]

In this study, we tested the hypothesis that human neutrophil alpha-defensins (HNPs) inhibit hepatic glucose production through a signaling pathway distinct from insulin. The effect of HNP-1 on fasting blood glucose levels and the expression of hepatic gluconeogenic genes was first examined. Using hyperinsulinemic-euglycemic clamps, we determined the effect of HNP-1 on endogenous glucose production, hepatic expression of key gluconeogenic genes and glucose uptake in skeletal muscle in Zucker diabetic fatty rats. In isolated primary hepatocytes, we studied the effect of HNP-1 and -2 on glucose production, expression of gluconeogenic genes, and phosphorylation of Akt, c-Src, and FoxO1. Our results show that HNP-1 reduced blood glucose levels of both normal mice and Zucker diabetic fatty rats predominantly through suppression of hepatic glucose production. HNPs inhibited glycogenolysis and gluconeogenesis in isolated hepatocytes. HNPs also suppressed expression of key gluconeogenic genes including phosphoenoylpyruvate carboxyl kinase and glucose-6-phosphatase. To investigate the mechanism, we found that HNPs stimulated phosphorylation of Akt and FoxO1 without activating IRS1. Nevertheless, HNPs activated c-Src. Blockade of c-Src activity with either a chemical inhibitor PP2 or an alternative inhibitor CSK prevented the inhibitory effect of HNPs on gluconeogenesis. Together, our results support the hypothesis that HNPs can suppress hepatic glucose production through an intracellular mechanism distinct from the classical insulin signaling pathway.

p38 mitogen-activated protein kinase (p38) is a member of MAP kinase family. Its wide-spectrum roles in the control of energy metabolism have been indicated in numerous studies. p38 participates in the energy metabolism in all major tissues/organs involved in the control of energy metabolism, including adipose tissue, skeletal muscles, islet cells, and liver. In white adipose tissue, p38 plays an important role in adipose differentiation and glucose uptake although it is still inconclusive whether this role of p38 is stimulatory or inhibitory. The stimulatory role of p38 in transcription of the uncoupling protein 1 (UCP1) gene in brown adipose tissue is relatively clear. A fundamental role for p38 in the differentiation of skeletal muscles and mitochondrial biogenesis in skeletal muscles is rather definitive although the role of p38 in glucose uptake of skeletal muscles remains controversial. In islet cells, p38 appears to be involved in beta-cell apoptosis. p38 has been indicated in the control of preproinsulin gene transcription, but remains controversial. However, it seems clear that p38 does not play a significant role in insulin secretion. In the liver, p38 plays a central role in hepatic glucose and lipid metabolism. Activation of p38 participates in the processes to increase blood glucose levels through reducing glycogen synthesis and increasing hepatic gluconeogenesis. p38 appears to prevent fat storage by inhibiting hepatic lipogenesis and promoting fatty acid oxidation in the liver. Additionally, p38 may play a critical role in cholesterol metabolism by regulating expression of the LDLR gene and bile metabolism. p38 does not only participate in various physiological and pathophysiological processes in cardiomyocytes, but also is heavily involved in the development of atherosclerotic lessions through its influences on monocytes/macrophages, vascular endothelial cells, and vascular smooth muscle cells.