p38 Mitogen-activated Protein Kinase Plays a Stimulatory Role in Hepatic Gluconeogenesis

Cao, Wenhong; Collins, Qu Fan; Becker, Thomas; Robidoux, Jacques; Lupo, Edgar G.; Xiong, Yan; Daniel, Kiefer W.; Floering, Lisa M.; Collins, Sheila

doi:10.1074/jbc.m506223200

Cited by 127 publications

(135 citation statements)

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“…Phosphorylation of p38 in the liver was increased by fasting and inhibited by SB (Fig. 3B) as expected (27). These results indicate that activation of p38 in liver is related to the reduction of transcript levels of central lipogenic genes, SREBP-1c, and its downstream target genes.…”

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatsupporting

confidence: 58%

“…Accumulation in Liver-During our study on the stimulatory role of p38 in hepatic gluconeogenesis (27), we unexpectedly observed that p38 might inhibit hepatic lipogenesis. To fully characterize this observation, we examined the effect of p38 inhibition on levels of plasma lipids and liver TG content in mice.…”

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

“…The Blockade of p38 Can Increase Transcript Levels of Lipogenic Genes in Fasted Liver-To investigate the possible role of p38 in suppression of hepatic lipogenesis, we chose to use fasting mice as models, because it is well known that hepatic lipogenesis is normally inhibited by fasting and p38 is activated in the liver during fasting (27). As expected (Fig.…”

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

“…The predominant suppressor of lipogenesis is glucagon, which is also the major promoter of hepatic glucose production and is always significantly elevated in the blood during fasting (35). Glucagon is a cAMP-producing hormone that can activate p38 in primary hepatocytes (27,36). To determine whether p38 mediates glucagon suppression of hepatic lipogenesis, levels of key lipogenic gene transcripts and phosphorylation of p38 in primary hepatocytes were examined in the presence or absence of p38 blockade.…”

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

“…Essentially, any significant change in extracellular environment can activate p38 and set in motion certain protective mechanisms, such as activation and production of heat shock proteins, immune responses, and apoptosis. We and others have recently shown that p38 plays an important role in the control of energy balance in brown adipocytes, muscle cells, and hepatocytes (23)(24)(25)(26)(27)(28). In this study, we investigated the role of p38 in the control of hepatic lipogenesis.…”

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confidence: 99%

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p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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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-1␤ 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-1␤ 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-1␤ and hepatic lipogenesis.Hepatic lipogenesis is essential for maintaining energy balance (1). Disorders of hepatic lipogenesis may lead to fatty liver, dyslipidemia, type II diabetes mellitus, and complications such as atherosclerosis (2). Lipogenesis in liver includes de novo synthesis of fatty acids and cholesterols. As a major site for synthesis of fatty acids, the liver converts excess carbohydrates into fat storage in the fed state. Fatty acids synthesized in the liver are converted into triglycerides and secreted as very low density lipoproteins, which transport fatty acids to the storage sites in adipocytes. Cholesterols synthesized in the liver are also transported to other tissues via very low density lipoproteins as essential building materials for steroid hormones and cellular membranes. However, excess production of fatty acids and cholesterols from the liver may contribute to a variety of lipid disorders. The lipogenic process in the liver is primarily regulated by central lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs) 2 (reviewed in Refs. 3 and 4).The SREBPs are basic helix-loop-helix-leucine zipper-containing transcription factors (5). Among three known SREBPs, SREBP-1a and -1c are encoded by the same gene; SREBP-1c lacks the N-terminal exon compared with SREBP-1a (6). SREBP-2 is encoded by a separate gene (7). Although SREBPs share similar lip...

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Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatsupporting

confidence: 58%

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

mentioning

confidence: 99%

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p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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Energy Metabolism in the Liver

Rui

2014

Comprehensive Physiology

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The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD).

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Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor κb pathway

et al. 2009

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Acute exposure to lipopolysaccharide (LPS) can cause hypoglycemia and insulin resistance; the underlying mechanisms, however, are unclear. We set out to determine whether insulin resistance is linked to hypoglycemia through Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor B (NF B), a cell signaling pathway that mediates LPS induction of the proinflammatory cytokine tumor necrosis factor alpha (TNF␣). LPS induction of hypoglycemia was blocked in TLR4 ؊/؊ and MyD88 ؊/؊ mice but not in TNF␣ ؊/؊ mice. Both glucose production and glucose utilization were decreased during hypoglycemia. Hypoglycemia was associated with the activation of NF B in the liver. LPS inhibition of glucose production was blocked in hepatocytes isolated from TLR4 ؊/؊ and MyD88 ؊/؊ mice and hepatoma cells expressing an inhibitor of NF B (I B) mutant that interferes with NF B activation. Thus, LPS-induced hypoglycemia was mediated by the inhibition of glucose production from the liver through the TLR4, MyD88, and NF B pathway, independent of LPS-induced TNF␣. LPS suppression of glucose production was not blocked by pharmacologic inhibition of the insulin signaling intermediate phosphatidylinositol 3-kinase in hepatoma cells. Insulin injection caused a similar reduction of circulating glucose in TLR4 ؊/؊ and TLR4 ؉/؉ mice. These two results suggest that LPS and insulin inhibit glucose production by separate pathways. Recovery from LPS-induced hypoglycemia was linked to glucose intolerance and hyperinsulinemia in TLR4 ؉/؉ mice, but not in TLR4 ؊/؊ mice. Conclusion: Insulin resistance is linked to the inhibition of glucose production by the TLR4, MyD88, and NF B pathway. (HEPATOLOGY 2009;50:592-600.) L ipopolysaccharide (LPS) from Gram-negative bacterial infection can cause hypoglycemia and insulin resistance in both humans and mice; however, the underlying mechanisms are unclear. 1-5 Low levels of LPS exposure through gastrointestinal tract and airborne particles can also lead to insulin resistance. 6-8 Thus, insulin resistance is decreased in mice by antibiotic treatment or housing in germ-free facilities. 9,10 Insulin resistance is also decreased by gene deletion of Toll-like receptor-4 (TLR4) or cluster of differentiation 14 (CD14), a glycoprotein that binds to the extracellular portion of TLR4. [11][12][13] TLR4 is a plasma membrane protein that mediates LPS induction of inflammatory cytokines such as tumor necrosis factor alpha (TNF␣) and interleukin-1 beta (IL-1␤). 14 The main goals of this study were to (1) determine whether TLR4 and its downstream signaling targets mediate the induction of hypoglycemia by LPS and, if so, (2) determine whether the induction of hypoglycemia by TLR4 is linked to the development of insulin resistance.LPS was postulated to cause hypoglycemia through the induction of the cytokines TNF␣ and IL-1␤. 15 Given that LPS does not induce hypoglycemia in IL-1␣ Ϫ/Ϫ and IL-1␤ Ϫ/Ϫ "double-knockout" mice, LPS induction of IL-1␤ is essential. 16 Whether LPS induction of TNF␣

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p38 Mitogen-activated Protein Kinase Plays a Stimulatory Role in Hepatic Gluconeogenesis

Cited by 127 publications

References 50 publications

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Energy Metabolism in the Liver

Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor κb pathway

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