Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt(+/+)) and knock-out (Pemt(-/-)) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt(-/-) mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver.
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PMID:Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action. 2317 47

FcgRIIB dysfunction is commonly found in patients with lupus, especially in Asia. LPS-tolerance is prominent in FcgRIIB-/- lupus mice. LPS-tolerant macrophages demonstrate cell energy depletion, which might affect lipid metabolism. Therefore, to explore lipid metabolism, LPS-tolerance was induced twice by LPS administration in macrophages and in mice. LPS-tolerant FcgRIIB-/- macrophages demonstrated lesser mitochondrial DNA (mtDNA), more severe ATP depletion, lower cytokine production, and higher lipid accumulation (oil red O staining) compared to LPS-tolerant WT cells. Mass-spectrometry-based lipidomic analysis demonstrated a higher abundance of phosphatidylethanolamine (PE) phospholipid in LPS-tolerant FcgRIIB-/- macrophages than WT cells. This was at least in part due to the lower expression of phosphatidylethanolamine N-methyltransferase (pemt), an enzyme that converts PE to phosphatidylcholine (PC). Aminoimidazole-4-carboxamide ribonucleotide (AICAR), a pemt inhibitor, worsens LPS-tolerance in WT macrophages and supports the impact of pemt upon LPS-tolerant FcgRIIB-/- macrophages. Additionally, phosphorylated AMP-activated protein kinase (AMPK-p), a molecule for ATP-restoration associated with pemt, and phosphorylated acetyl CoA carboxylase, a downstream signaling of AMPK-p, were higher in LPS-tolerant FcgRIIB-/- macrophages than WT. Furthermore, Compound C, an AMPK inhibitor, attenuated LPS-tolerance in both FcgRIIB-/- macrophages and mice. Taken together, the intense decrease in cytokine production after the second LPS stimulation (LPS-tolerance) in FcgRIIB-/- macrophages was possibly due to the impact of an immense cytokine synthesis after the first dose of LPS. This includes using up PEMT, an enzyme of phospholipid synthesis during cytokine production, and AMPK-p induction in response to profound ATP-depletion. Therefore, the manipulation of the AMPK/PEMT axis provides a novel therapeutic candidate for the treatment of severe LPS-tolerance in lupus.
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PMID:Dysregulation of Lipid Metabolism in Macrophages Is Responsible for Severe Endotoxin Tolerance in FcgRIIB-Deficient Lupus Mice. 3258 49