Induction by interleukin 6 of Gs-coupled prostaglandin E2 receptors in rat hepatocytes mediating a prostaglandin E2–dependent inhibition of the hepatocyte's acute phase response

Fennekohl, Alexandra; Lucas, María; Püschel, Gerhard

doi:10.1053/he.2000.7055

Cited by 34 publications

(23 citation statements)

References 43 publications

(50 reference statements)

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“…127 In this regard, PGE 2 also inhibits liver lipolysis, b-oxidation, and very low density lipoprotein synthesis further contributing to obesity, 128 yet the EP receptor is unknown. This lipid-accumulating effect of PGE 2 on hepatocyte lipid metabolism has been recognized for quite some time [129][130][131][132][133][134] ; however, it has also been demonstrated that PGE 2 derived from nonparenchymal liver cells attenuates insulin responses in the hepatocyte. 124 COX-2 derived PGE 2 also inhibits pancreatic insulin secretion, and COX-2 inhibitors and EP 3 antagonists improved b-cell function in mice, resulting in enhanced insulin release and glucose tolerance after a glucose challenge.…”

Section: Pge 2 In Other Aspects Of the Metabolic Syndromementioning

confidence: 99%

PGE2, Kidney Disease, and Cardiovascular Risk

Nasrallah

Hassouneh

Hébert

2016

Journal of the American Society of Nephrology

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An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE 2 in these events. This review summarizes the role of PGE 2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE 2 signaling in hypertension and diabetes, and outlines the contribution of PGE 2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE 2 could lead to new avenues to improve therapeutic options and disease management strategies. 27: 666-676, 201627: 666-676, . doi: 10.1681 Accelerated cardiovascular disease is the leading cause of mortality in patients with kidney disease. 1,2 This implies that kidney disease has a major effect on global cardiovascular risk, affecting fluid (volume, BP), electrolyte, and acid base balance, among many other cardiovascular risk factors. In fact, renal transplantation ameliorates cardiovascular risk, improves quality of life, and reduces mortality. 2 PGs are important homeostatic regulators of kidney function. PGE 2 is the major product of cyclooxygenase (COX)-2 and microsomal PGE synthase 1 (mPGES1), and both of these enzymes are elevated in renal diseases. [3][4][5][6][7][8][9][10] PGE 2 binds four EP receptors (EP 1-4 ) to activate G protein signaling responses. Figure 1 illustrates the COX pathway leading to PGE 2 , as well as its target receptors. These receptors are often coexpressed in cells and usually have opposing effects (protective and harmful). PGE 2 acting on EP can alter vascular tone and influence renal blood flow and hemodynamics. 11-15 PGE 2 also stimulates the macula densa to activate the renin-angiotensin-aldosterone system, a key mediator of kidney injury. [16][17][18][19] Inflammatory, immune, and oxidative stress responses are influenced by PGE 2 , which are reported to alter growth, fibrosis, and apoptosis in renal cells. 20-26 PGE 2 also contributes to disturbances in collecting duct salt and water transport in polyuric diseases, 19,[27][28][29] and b cell defects in sodium and potassium handling associated with type I distal renal tubule acidosis. 30 PGE 2 /EP 4 also compensates for the loss of vasopressin V2 receptors in mouse diabetes insipidus. 28 Although attempts to block PGE 2 using COX-2 or mPGES1 inhibitors have failed, selective inhibition of EP receptors may prove to be quite useful in controlling the deleterious effects of COX-2/mPGES1/PGE 2 , while leaving the protective responses intact. EP 1 mediates many of the pathologic effects of PGE 2 in kidne...

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Section: Pge 2 In Other Aspects Of the Metabolic Syndromementioning

confidence: 99%

PGE2, Kidney Disease, and Cardiovascular Risk

Nasrallah

Hassouneh

Hébert

2016

Journal of the American Society of Nephrology

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“…Prostaglandins mediate many of their protean biological activities by binding to G protein coupled transmembrane receptors, which modulate cAMP signaling (36). The action of cAMP is in part mediated by its binding to and activation of a protein kinase which, in turn, phosphorylates and activates the DNA binding protein CREB, the cAMP response element binding protein.…”

Section: Relationship Between Prostaglandin Signaling and Camp-signalingmentioning

confidence: 99%

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Rudnick

Perlmutter

Muglia

2001

Proc. Natl. Acad. Sci. U.S.A.

121

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The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to partial hepatectomy has been used as a model system to elucidate the molecular basis of this regenerative response. In this study, we used cyclooxygenase (COX)-selective antagonists and -null mice to determine the role of prostaglandin signaling in the response of liver to partial hepatectomy. The results show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activation of signal transducer and activator of transcription-3 (STAT3) that is seen during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data indicate that prostaglandin signaling is required during liver regeneration, that COX-2 plays a particularly important role but COX-1 is also involved, and implicate the activation of CREB rather than STAT3 as the mediator of prostaglandin signaling during liver regeneration.

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“…5,6 Prostaglandins may affect hepatocyte metabolism directly 7 or they can modulate the regulation of hepatocyte metabolism by hormones 8,9 or cytokines. 10,11 There are conflicting reports about the impact of prostaglandins on hepatic lipid metabolism. Although some studies indicate that prostaglandins might favor fat accumulation in hepatocytes and hence the development of hepatic steatosis, 12 others provide evidence that PGE 2 rather might suppress de novo lipogenesis 13 or that PGE 2 does not affect lipogenesis but attenuate triglyceride incorporation into VLDL.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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Induction by interleukin 6 of Gs-coupled prostaglandin E2 receptors in rat hepatocytes mediating a prostaglandin E2–dependent inhibition of the hepatocyte's acute phase response

Cited by 34 publications

References 43 publications

PGE2, Kidney Disease, and Cardiovascular Risk

PGE2, Kidney Disease, and Cardiovascular Risk

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

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