Malonyl‐CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5′AMP‐activated protein kinase (AMPK)

Sambandam, Nandakumar; Steinmetz, Michael; Chu, Angel; Altarejos, Judith Y.; Dyck, Jason R.B.; Lopaschuk, Gary D.

doi:10.1111/j.1432-1033.2004.04218.x

Cited by 52 publications

(39 citation statements)

References 45 publications

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“…Nevertheless, the fact that DN-AMPK prevented the effects of metformin is strong evidence that its actions are primarily mediated by AMPK. This is also consistent with accumulating evidence that AMPK regulates the key enzymes that control lipid biosynthesis, such as glycerol-3-phosphate acyltransferase and malonylCoA decarboxylase (42,48,49). The fact that the actions of metformin in HepG2 cells were completely abrogated by the DN-AMPK makes this hepatocellular model of insulin resistance ideal for identifying other agents that affect lipid metabolism via AMPK.…”

Section: Actions Of Metformin In a Hepatocellular Model Of Insulinsupporting

confidence: 63%

AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells

Zang

Zuccollo

Hou

et al. 2004

Journal of Biological Chemistry

419

352

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The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the ␣ subunit of AMPK in a dose-and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviralmediated expression of a constitutively active AMPK␣ or a kinase-inactive AMPK␣, respectively. An insulinresistant state was induced by exposing cells to 30 mM glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3␣/␤. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPK␣. The kinase-inactive AMPK␣ increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPK␣ negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance. AMP-activated protein kinase (AMPK)1 is a phylogenetically conserved intracellular energy sensor that has been implicated in the regulation of glucose and lipid homeostasis (1-4). AMPK is activated by physiological stimuli, such as exercise, muscle contraction, and hormones including adiponectin and leptin, as well as by pathological stresses, glucose deprivation, hypoxia, oxidative stress, and osmotic shock (2, 5). AMPK serine/threonine protein kinase is a heterotrimeric complex consisting of a catalytic subunit (␣) and two regulatory subunits (␤ and ␥) (5). Regulation of AMPK activity is complex; it involves allosteric activation by AMP, which increases during states of stress where ATP is depleted, and phosphorylation via the presumptive upstream activator AMPK kinase (6 -9), which may also be allosterically activated by AMP (5). Moreover, phosphorylation of Thr-172 within the activation loop of the catalytic domain of the ␣ subunit is necessary for AMPK activity because sitedirected mutagenesis of Thr-172 to Ala completely abolishes AMPK activity (10, 11). Once activated, AMPK phosphorylates its downstream substrates to reduce ATP-consuming anabolic pathways, including ...

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Section: Actions Of Metformin In a Hepatocellular Model Of Insulinsupporting

confidence: 63%

AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells

Zang

Zuccollo

Hou

et al. 2004

Journal of Biological Chemistry

419

352

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“…AMPK activity assay was performed as previously described (39). Tissues (20 mg) were cut and homogenized in 200 l of homogenization buffer containing 50 mM Tris ⅐ HCl (pH 8) at 4°C, 1 mM EDTA, 10% (wt/vol) glycerol, 0.02% (vol/vol) Brij-35, 1 mM dithiothreitol, protease inhibitor (Sigma), and phosphatase inhibitor (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Cui¹,

Paglialunga²,

Kalant³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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August 21, 2007; doi:10.1152/ajpendo.00565.2006.-Acylation-stimulating protein (ASP), a lipogenic hormone, stimulates triglyceride (TG) synthesis and glucose transport upon activation of C5L2, a G protein-coupled receptor. ASP-deficient mice have reduced adipose tissue mass due to increased energy expenditure despite increased food intake. The objective of this study was to evaluate the blocking of ASP-C5L2 interaction via neutralizing antibodies (anti-ASP and anti-C5L2-L1 against C5L2 extracellular loop 1). In vitro, anti-ASP and anti-C5L2-L1 blocked ASP binding to C5L2 and efficiently inhibited ASP stimulation of TG synthesis and glucose transport. In vivo, neither anti-ASP nor anti-C5L2-L1 altered body weight, adipose tissue mass, food intake, or hormone levels (insulin, leptin, and adiponectin), but they did induce a significant delay in TG clearance [P Ͻ 0.0001, 2-way repeated-measures (RM) ANOVA] and NEFA clearance (P Ͻ 0.0001, 2-way RM ANOVA) after a fat load. After treatment with either anti-ASP or anti-C5L2-L1 antibody there was no change in adipose tissue AMPK activity, but neutralizing antibodies decreased perirenal TG mass (Ϫ38.4% anti-ASP, Ϫ18.8% anti-C5L2, P Ͻ 0.01-0.001) and perirenal LPL activity (Ϫ75.6% anti-ASP, Ϫ72.5% anti-C5L2, P Ͻ 0.05). In liver, anti-C5L2-L1 decreased TG mass (Ϫ42.8%, P Ͻ 0.05), whereas anti-ASP increased AMPK activity (ϩ34.6%, P Ͻ 0.001). In the muscle, anti-C5L2-L1 significantly increased TG mass (ϩ128.0%, P Ͻ 0.05), LPL activity (ϩ226.1%, P Ͻ 0.001), and AMPK activity (ϩ71.1%, P Ͻ 0.01). In addition, anti-ASP increased LPL activity (ϩ164.4, P Ͻ 0.05) and AMPK activity (ϩ53.9%, P Ͻ 0.05) in muscle. ASP/C5L2-neutralizing antibodies effectively block ASP-C5L2 interaction, altering lipid distribution and energy utilization. lipoprotein lipase; adenosine 5Ј-monophosphate-activated protein kinase; dietary fat partitioning; fatty acid reesterification; C3adesArg

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“…. AMPK activates MCD (Sambandam et al 2004). Through modulating AMPK signaling, glucagon increases MCD activity, promoting conversion of malonyl-CoA to acetyl-CoA and relieving CPT1 inhibition, while insulin inhibits MCD activity and reduces CPT1 activity (Dyck et al 2000).…”

Section: The Interplay Of Dnl and Beta-oxidationmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

156

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Malonyl‐CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5′AMP‐activated protein kinase (AMPK)

Cited by 52 publications

References 45 publications

AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells

AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells

Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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