The regulation of mitochondrial-bound hexokinases in the liver

Weiler, U.; Riesinger, I.; Knoll, Gerd; Brdiczka, Dieter

doi:10.1016/0006-2944(85)90031-6

Cited by 55 publications

(18 citation statements)

References 26 publications

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“…Therefore, it is possible that HKII is more active after BPD, perhaps owing to a higher percentage of this isoform docked to the mitochondrial membrane. This hypothesis is supported by data in the literature showing that the activity of HK in vivo is much larger in the mitochondrial that in the cytosolic fraction; 36 the transition from one to the other HK form being mediated by insulin. 37 Furthermore, it has been demonstrated that in mice heterozygotes for HKII deficiency, a 50% reduction of both HKII mRNA and activity does not impair insulin action or glucose tolerance.…”

Section: Discussionsupporting

confidence: 62%

Molecular mechanisms of diabetes reversibility after bariatric surgery

et al. 2007

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Objective: Insulin resistance is a strong biological marker of both obesity and type 2 diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. Biliopancreatic diversion (BPD), inducing a massive lipid malabsorption, leads to a reversion of type 2 diabetes. To elucidate the mechanisms of diabetes reversibility, the expression of genes involved in glucose and free fatty acids (FFAs) metabolism was investigated in skeletal muscle biopsies from obese, type 2 diabetic subjects. Peripheral insulin sensitivity and insulin secretion was also measured. Subjects: Eight Caucasian obese diabetic patients (BMI 52.171.85 kg/m 2 ) were studied before and 3 years after BPD. Measurements: The mRNA levels were estimated by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), insulin sensitivity by the euglycemic-hyperinsulinemic clamp and insulin secretion using a model describing the relationship between insulin secretion and glucose concentration. Results: Whole-body glucose uptake (M), normalized by fat-free mass, significantly increased in post-obese subjects (Po0.0001). Total insulin output decreased (Po0.05) in association with a significant improvement of b-cells glucose sensitivity (Po0.05). mRNA levels of FABP3 (Po0.05), FACL (Po0.05), ACC2 (Po0.05), HKII (Po0.05) and PDK4 (Po0.05) were significantly decreased, while SREBP1c mRNA increased (Po0.05) after BPD. Conclusion: Reversibility of type 2 diabetes after BPD is dependent on the improvement of skeletal muscle insulin sensitivity, mediated by changes in the expression of genes regulating glucose and fatty acid metabolism in response to nutrient availability.

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Section: Discussionsupporting

confidence: 62%

Molecular mechanisms of diabetes reversibility after bariatric surgery

et al. 2007

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“…This change might represent an immediate adaptive response and is thought to couple glucose phosphorylation to the mitochondrial ATP-generating system. The association of hexokinase with the mitochondrial membrane has been reported to result in a pronounced increase in the specific hexokinase activity in rat liver [35,361. The second mechanism contributing to an augmented glucose In normal fast-twitch muscle, glycogen breakdown represents thc major source of glucose 6-phosphate for glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Changes in free and bound forms and total amount of hexokinase isozyme II of rat muscle in response to contractile activity

Weber

Pette

1990

European Journal of Biochemistry

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Increased contractile activity as induced by chronic low-frequency stimulation evoked in rat fast-twitch muscle an almost immediate increase in the ratio between structure-bound and free hexokinase. In addition, an up to 14-fold rise in total hexokinase activity occurred after two weeks of stimulation indicating that glucose phosphorylation became a limiting step of glucose utilization under these conditions. The increase in hexokinase activity was transitory as prolonged stimulation led to a leveling off and steep decline with an apparent half-life of 2.5 days after three weeks of stimulation. The transient increase in glucose phosphorylating capacity can be explained by previous observations indicating that prolonged stimulation leads to a shift from a carbohydrate-based to a fattyacid-based energy metabolism. Using an isozyme-specific sandwich ELISA, it was shown that both increases and decreases in total hexokinase activity were matched by corresponding changes in the amount of hexokinase isozyme 11 protein. Increases in both total hexokinase activity (3 -4-fold) and hexokinase I1 protein content were also observed after denervation in rat fast-twitch muscle. In view of reports in the literature, it is suggested that the elevations in hexokinase I1 observed with increased contractile activity and denervation relate to enhanced glucose uptake and utilization.Increased contractile activity as induced by chronic lowfrequency stimulation of fast-twitch muscle, leads to a profound rearrangement of the enzyme activity pattern of energy metabolism. In the rabbit, glycolytic enzyme activities decrease, whereas enzyme activities related to mitochondrial pathways of aerobic-oxidative metabolism increase [l -91. In contrast to the other glycolytic enzymes, hexokinase activity increases under these conditions. Therefore, hexokinase behaves in a similar manner as the enzymes of substrate end oxidation [l, 2, 5-10]. However, time course studies show that its increase precedes that of the mitochondrial enzyme activities [2, 61. In view of the very low activity of hexokinase in fast-twitch muscles [ll], its rapid rise could indicate that glucose phosphorylation becomes a limiting step of fuel supply under the conditions of persistently increased contractile activity. Contractile activity appears thus to be an important factor in regulating the cellular content of hexokinase in skeletal muscle. In this connection, the following questions are of interest. (a) Is the increase in total hexokinase activity caused by a modification of the enzyme or does it result from an increase in protein amount, e.g. due to changes in synthesis and/or degradation? (b) Is the increase in total hexokinase activity related to changes in the cellular level of one or several isozymes? (c) Does increased contractile activity also affect the binding of hexokinase to the mitochondria? In order to address these questions, we have studied the time course of stimulation-induced changes in total hexokinase activity as well as in the amount of hexokinase i...

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“…Hexokinase distribution at the mitochondrial surface studied by electron microscopic techniques, and by removing unattached outer membrane with digitonin, led to preferential localisation of the enzyme in the contact sites [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

et al. 1996

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In vitro incubation of isolated hexokinase isozyme I or isolated dimer of mitochondrial creatine kinase with the outer mitochondrial membrane pore led to high molecular weight complexes of enzyme oligomers. Similar complexes of hexokinase and mitochondrial creatine kinase could be extracted by 0.5% Triton X-100 from homogenates of rat brain. Hexokinase and creatine kinase complexes could be separated by subsequent chromatography on DEAE anion exchanger. The molecular weight, as determined by gel-permeation chromatography, was approximately 400 kDa for both complexes. The Mr suggested tetramers of hexokinase (monomer 100 kDa) and creatine kinase (active enzyme is a dimer of 80 kDa). The composition of the complexes was further characterised by specific antibodies. Besides either hexokinase or creatine kinase molecules the complexes contained porin and adenylate translocator. It was possible to incorporate the complexes into artificial bilayer membranes and to measure conductance in 1 M KCI. The incorporating channels had a high conductance of 6 nS that was asymmetrically voltage dependent. The complexes were also reconstituted in phospholipid vesicles that were loaded with ATP. Complex containing vesicles retained ATP while vesicles reconstituted with pure porin were leaky. The internal ATP could be used by creatine kinase and bexokinase in the complex to phosphorylate external creatine or glucose. This process was inhibited by atractyloside. The hexokinase complex containing vesicles were furthermore loaded with malate or ATP that was gradually released by addition of Ca 2+ between 100 and 600 IJNI. The liberation of malate or ATP by Ca 2+ could be inhibited by N-methylVal-4-cyclosporin, suggesting that the porin translocator complex constitutes the permeability transition pore. The results show the physiological existence of kinase porin translocator complexes at the mitochondrial surface. It is assumed that such complexes between inner and outer membrane components are the molecular basis of contact sites observed by electron microscopy. Kinase complex formation may serve three regulatory functions, firstly regulation of the kinase activity, secondly stimulation of oxidative phosphorylation and thirdly regulation of the permeability transition pore.

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The regulation of mitochondrial-bound hexokinases in the liver

Cited by 55 publications

References 26 publications

Molecular mechanisms of diabetes reversibility after bariatric surgery

Molecular mechanisms of diabetes reversibility after bariatric surgery

Changes in free and bound forms and total amount of hexokinase isozyme II of rat muscle in response to contractile activity

Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore

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