D. S. Rubink
Bio: D. S. Rubink is an academic researcher from Brigham Young University. The author has contributed to research in topics: AMP-activated protein kinase & AMPK. The author has an hindex of 3, co-authored 3 publications receiving 331 citations.
TL;DR: Data provide the first evidence of a direct link between extent of phosphorylation of these proteins at sites recognized by the antibodies and activity of the enzymes in electrically stimulated muscle and in muscle of rats running on the treadmill.
Abstract: AMP-activated protein kinase (AMPK) is activated during muscle contraction in response to the increase in AMP and decrease in phosphocreatine (PCr). Once activated, AMPK has been proposed to phosph...
TL;DR: Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK, which may contribute to low-muscle malonyl- CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.
Abstract: AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-Co...
TL;DR: Evidence is provided that some effects of denervation may be prevented by chemical activation of the appropriate signaling pathways as well as the extent ofDenervation-induced muscle atrophy was similar in AICAR-treated vs. saline-treated rats.
Abstract: This study was designed to determine whether the reductions in GLUT-4 seen in 3-day-denervated muscles can be prevented through chemical activation of 5′-AMP-activated protein kinase (AMPK). Muscle...
TL;DR: It is shown that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser428, and AMPK activity, which suggests that Sirt1 functions as a novel upstream regulator for L KB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism.
Abstract: Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser428, and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKβ, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.
TL;DR: It is revealed that inactivation of hepatic AMPK is a key event in the pathogenesis of hyperlipidemia in diabetes, point to a novel mechanism of action of polyphenols to lower lipids by activating AMPK, and emphasize a new therapeutic avenue to benefit hyper Lipidemia and atherosclerosis specifically in diabetes.
Abstract: Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMP-activated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor-deficient mice (DMLDLR(-/-)). In HepG2 hepatocytes, polyphenols, including resveratrol (a major polyphenol in red wine), apigenin, and S17834 (a synthetic polyphenol), increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC), and they increased activity of AMPK with 200 times the potency of metformin. The polyphenols also prevented the lipid accumulation that occurred in HepG2 cells exposed to high glucose, and their ability to do so was mimicked and abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Furthermore, treatment of DMLDLR(-/-) mice with S17834 prevented the decrease in AMPK and ACC phosphorylation and the lipid accumulation in the liver, and it also inhibited hyperlipidemia and the acceleration of aortic lesion development. These studies 1) reveal that inactivation of hepatic AMPK is a key event in the pathogenesis of hyperlipidemia in diabetes, 2) point to a novel mechanism of action of polyphenols to lower lipids by activating AMPK, and 3) emphasize a new therapeutic avenue to benefit hyperlipidemia and atherosclerosis specifically in diabetes via activating AMPK.
01 Jan 1995
TL;DR: In this article, the effects of contraction and insulin on the GLUT4glucose transporter translocation were investigated in ratsoleus muscles by using a 3-O-methylGLucose transport assay and a sensitive exofa-ciallabeling technique with the impermeant photoaffinity reagent 2-N-4-(1-azi-2, 2,2,2-trifluoroethy l)benzoyl-1,3-bis(D- mannose-4-yloxy)-2-pro
Abstract: Theacute effects ofcontraction andinsulin ontheglucose transport andGLUT4glucose transporter translocation wereinvestigated inratsoleus muscles byusing a3-O-methylglucose transport assay andthesensitive exofa- ciallabeling technique withtheimpermeant photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethy l)benzoyl-1,3-bis(D- mannose-4-yloxy)-2-propylamine (ATB-BMPA), respectively. Addition ofwortmannin, whichinhibits phosphatidylinositol 3-kinase, reduced insulin-stimulated
TL;DR: This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors.
Abstract: Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.
TL;DR: Results indicate that ACC beta phosphorylation is especially sensitive to exercise and tightly coupled to AMPK signaling and that AMPK activation does not depend on AMPK kinase activation during exercise.
Abstract: The effect of exercise intensity on skeletal muscle AMP-activated protein kinase (AMPK) signaling and substrate metabolism was examined in eight men cycling for 20 min at each of three sequential intensities: low (40 +/- 2% VO(2) peak), medium (59 +/- 1% VO(2) peak), and high (79 +/- 1% VO(2) peak). Muscle free AMP/ATP ratio only increased at the two higher exercise intensities (P < 0.05). AMPK alpha 1 (1.5-fold) and AMPK alpha 2 (5-fold) activities increased from low to medium intensity, with AMPK alpha 2 activity increasing further from medium to high intensity. The upstream AMPK kinase activity was substantial at rest and only increased 50% with exercise, indicating that, initially, signaling through AMPK did not require AMPK kinase posttranslational modification. Acetyl-CoA carboxylase (ACC)-beta phosphorylation was sensitive to exercise, increasing threefold from rest to low intensity, whereas neuronal NO synthase (nNOS) micro phosphorylation was only observed at the higher exercise intensities. Glucose disappearance (tracer) did not increase from rest to low intensity, but increased sequentially from low to medium to high intensity. Calculated fat oxidation increased from rest to low intensity in parallel with ACC beta phosphorylation, then declined during high intensity. These results indicate that ACC beta phosphorylation is especially sensitive to exercise and tightly coupled to AMPK signaling and that AMPK activation does not depend on AMPK kinase activation during exercise.