Detailed molecular analysis of the induction of the L-PK gene by glucose

Eckert, David; Zhang, Pili; Collier, J. Jason; O’Doherty, Robert M.; Scott, Donald K.

doi:10.1016/j.bbrc.2008.05.002

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…These data are in consistence with results of other studies [5,20,21]. The increase of glucose blood level should stimulate liver pyruvate kinase expression [6]. In case of 2.5g/kg of ethanol intake the indirect inhibition by ethanol seemed to be compensated by the indirect activation associated with increase of glucose blood level.…”

Section: Glucose Blood Levels In Rats During Acute and Chronic Alcohosupporting

confidence: 90%

“…One of the possible pathways of indirect liver pyruvate kinas activity regulation is a pathway linked to glucose blood level [6]. According to our results (see section 3.10) glucose blood level was elevated during chronic alcohol intoxication as well as after the intake of average or high bolus dose of ethanol.…”

Section: Discussionsupporting

confidence: 57%

“…Activity of liver pyruvate kinase, unlike that of muscle pyruvate kinase, is also regulated in indirect manner by such hormones as insulin (it activates liver pyruvate kinase promoting its dephosphorylation), epinephrine and glucagon (they deactivate liver pyruvate kinase promoting its phosphorylation) [2]. Moreover, glucose itself is able to promote expression of the gene coding for liver pyruvate kinase [6]. So, elevated glucose blood level is a signal leading to the increase of liver pyruvate kinase expression.…”

Section: Discussionmentioning

confidence: 99%

“…Even though those two enzymes share a high degree of similarity in primary and, especially, in secondary and tertiary structures, enzymatic activity of the muscle pyruvate kinase is approximately 10 times higher than that of the liver pyruvate kinase. It is known that liver pyruvate kinase is a subject of indirect activity regulation by insulin [5,26], glucagon [2], epinephrine and even glucose blood levels [6], while muscle pyruvate kinase is not.…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico

Vladimirovich¹,

Khrustalev²,

Victorovich³

et al. 2013

AJMBR

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The influence of ethanol on enzymatic activities of muscle and liver pyruvate kinases has been studied in rats in series of in vivo and in vitro experiments accompanied by in silico study. Activity of muscle pyruvate kinase significantly decreased in experiments on acute alcohol intoxication (5.0g/kg of body weight), during chronic alcohol consumption (3.5g/kg of body weight 2 times a day for 14 and 28 days) and during the abstinence after the period of alcohol consumption (5.0g/kg of body weight 2 times a day for 5 days). Activity of liver pyruvate kinase was not decreased in rats after the period of alcohol consumption (5.0g/kg of body weight 2 times a day for 5 days) and during chronic alcohol consumption (3.5g/kg of body weight 2 times a day for 28 days). It even became significantly higher during the chronic alcohol consumption (3.5g/kg of body weight 2 times a day) lasting for 14 days. Inhibitory effect of alcohol bolus on activities of both pyruvate kinases should be linked with certain indirect mechanisms, since direct inhibitory effect was seen in vitro only after the addition of 500 mM ethanol to the rat muscle and liver supernatants. Since lactate dehydrogenase is used in a coupled assay for pyruvate kinase activity estimation we approved that 500mM ethanol did not inhibit lactate dehydrogenase activity in human plasma. Direct inhibition of pyruvate kinases activities should be due to the ability of ethanol to bind amino acid residues from the known allosteric site for alanine binding on muscle and liver pyruvate kinases shown by us with the help of molecular docking. Indirect activation of liver pyruvate kinase can be explained by the increase of glucose blood levels in rats during alcohol consumption promoting dephosphorylation of the enzyme as well as expression of the gene coding for it, and the decrease of alanine concentration in liver.

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Section: Glucose Blood Levels In Rats During Acute and Chronic Alcohosupporting

confidence: 90%

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico

Vladimirovich¹,

Khrustalev²,

Victorovich³

et al. 2013

AJMBR

View full text Add to dashboard Cite

show abstract

“…36 The adult liver is characterized by expression of the L-type isoform. 37 In contrast, M2 is expressed predominantly during embryogenesis in the fetal liver and other rapidly dividing tissues. 38 In contrast to the adult isoforms, PKM2 diverts glucose metabolism to an alternate pathway that generates short carbon chains for molecular building blocks needed by rapidly dividing cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Hines

Hartwell

Feng

et al. 2011

The American Journal of Pathology

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Insulin resistance is a defining feature of metabolic syndrome and type 2 diabetes mellitus but also may occur independently of these conditions. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of these disorders, increases the risk of hepatocellular carcinoma (HCC). However, mechanisms linking hyperinsulinemia to NAFLD and HCC require clarification. We describe a novel model of primary insulin resistance and HCC with strong parent-of-origin effects. Male AB6F1 (A/JCr dam ؋ C57BL/6 sire) but not B6AF1 (B6 dam ؋ A/J sire) mice developed spontaneous insulin resistance, NAFLD, and HCC without obesity or diabetes. A survey of mitochondrial, imprinted, and sex-linked traits revealed modest associations with X-linked genes. However, a dietinduced obesity study, including B6.A chromosome substitution-strain (consomic) mice, showed no segregation by sex chromosome. Thus, parent-of-origin effects were specified within the autosomal genome. Next, we interrogated mechanisms of insulin-associated hepatocarcinogenesis. Steatotic hepatocytes exhibited adipogenic transition characterized by vacuolar metaplasia and up-regulation of vimentin, adipsin, fatty acid translocase (CD36), peroxisome proliferator-activated receptor-␥, and related products. This profile was largely recapitulated in insulin-supplemented primary mouse hepatocyte cultures. Importantly, pyruvate kinase M2, a fetal anabolic enzyme implicated in the Warburg effect, was activated by insulin in vivo and in vitro. Thus, our study reveals parent-of-origin effects in heritable insulin resistance, implicating adipogenic transition with acquired anabolic metabolism in the progression from NAFLD to HCC.

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Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors

Poupeau

Postic

2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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There is a worldwide epidemic of obesity and type 2 diabetes, two major public health concerns associated with alterations in both insulin and glucose signaling pathways. Glucose is not only an energy source but also controls the expression of key genes involved in energetic metabolism, through the glucose-signaling transcription factor, Carbohydrate Responsive Element Binding Protein (ChREBP). ChREBP has emerged as a central regulator of de novo fatty acid synthesis (lipogenesis) in response to glucose under both physiological and physiopathological conditions. Glucose activates ChREBP by regulating its entry from the cytosol to the nucleus, thereby promoting its binding to carbohydrate responsive element (ChoRE) in the promoter regions of glycolytic (L-PK) and lipogenic genes (ACC and FAS). We have previously reported that the inhibition of ChREBP in liver of obese ob/ob mice improves the metabolic alterations linked to obesity, fatty liver and insulin-resistance. Therefore, regulating ChREBP activity could be an attractive target for lipid-lowering therapies in obesity and diabetes. However, before this is possible, a better understanding of the mechanism(s) regulating its activity is needed. In this review, we summarize recent findings on the role and regulation of ChREBP and particularly emphasize on the cross-regulations that may exist between key nuclear receptors (LXR, TR, HNF4α) and ChREBP for the control of hepatic glucose metabolism. These novel molecular cross-talks may open the way to new pharmacological opportunities. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

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Detailed molecular analysis of the induction of the L-PK gene by glucose

Cited by 12 publications

References 32 publications

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors

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