LKB1 Regulates Lipid Oxidation During Exercise Independently of AMPK

Jeppesen, Jacob; Maarbjerg, Stine; Jordy, Andreas Børsting; Fritzen, Andreas M.; Pehmøller, Christian; Sylow, Lykke; Serup, Annette Karen; Jessen, Niels; Thorsen, Kasper; Prats, Clara; Qvortrup, Klaus; Dyck, Jason R.B.; Hunter, Roger W.; Sakamoto, Kei; Thomson, David M.; Schjerling, Peter; Wojtaszewski, Jørgen F. P.; Richter, Erik A.; Kiens, Bente

doi:10.2337/db12-1160

Cited by 69 publications

(117 citation statements)

References 50 publications

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“…Such an AMPK independent effect has recently been described in the muscle during exercise. 42 Furthermore, our results cannot fully exclude the possibility that Lkb1 deletion also results in a broader mitochondrial dysfunction, as was also evident by altered mitochondrial morphology and the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1a), a key regulator of mitochondrial biogenesis. Recent studies suggest that PGC1a is downregulated in bone marrow 43 and skeletal muscle cells 44,45 in the absence of Lkb1 deletion.…”

Section: Discussionmentioning

confidence: 39%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

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Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1 flox/flox ) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers b-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-a (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. 27: 439-453, 201627: 439-453, . doi: 10.1681 Renal tubular epithelial cells (TECs) display strict apico-basal polarity. They allow a highly regulated uptake or excretion of substances at its apical surface, while keeping a closed, impenetrable surface through the formation of tight intercellular junctions in the basolateral membrane. The establishment and maintenance of TEC polarity is incompletely understood. The liver kinase B1 (LKB1) is an important regular of polarity. Early studies indicated that single intestinal epithelial cells polarize in a cell-autonomous fashion in response to LKB1 expression. 1 The LKB1 or STK11 gene encodes an evolutionarily conserved serine/threonine protein kinase. Following LKB1 expression, intestinal epithelial cells reorganized their cytoskeleton to form an apical brush border, demonstrating LKB1's critical role in establishing epithelial polarity. On the other hand, the effect of LKB1 on cell polarity appears to be cell type specific and deletion of LKB1 did not alter polarity of lung epithelial and pancreatic cells. 2 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 39%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

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“…The normal basal activity of CS in AMPK␣ mdKO compared with WT mice is in agreement with our previous data in these mice (29) and previous data from AMPK␣2 KD mice (1). However, a decreased basal CS activity has been found in AMPK␣2 KO (25), AMPK␣2iTG (51), AMPK␤1␤2M-KO (48), LKB1 MKO (24,54), and skmLKB1-KO mice (52). Thus, although the majority of studies suggest that altered AMPK signaling plays a role in basal CS activity, it is clearly not the sole determinant.…”

Section: Discussionmentioning

confidence: 88%

AMPKα is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle

Fentz

Kjøbsted

Kristensen

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-Exercise training increases skeletal muscle expression of metabolic proteins improving the oxidative capacity. Adaptations in skeletal muscle by pharmacologically induced activation of 5=-AMP-activated protein kinase (AMPK) are dependent on the AMPK␣2 subunit. We hypothesized that exercise training-induced increases in exercise capacity and expression of metabolic proteins, as well as acute exercise-induced gene regulation, would be compromised in muscle-specific AMPK␣1 and -␣2 double-knockout (mdKO) mice. An acute bout of exercise increased skeletal muscle mRNA content of cytochrome c oxidase subunit I, glucose transporter 4, and VEGF in an AMPK-dependent manner, whereas cluster of differentiation 36 and fatty acid transport protein 1 mRNA content increased similarly in AMPK␣ wild-type (WT) and mdKO mice. During 4 wk of voluntary running wheel exercise training, the AMPK␣ mdKO mice ran less than WT. Maximal running speed was lower in AMPK␣ mdKO than in WT mice but increased similarly in both genotypes with exercise training. Exercise training increased quadriceps protein content of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), cytochrome c, hexokinase II, plasma membrane fatty acid-binding protein, and citrate synthase activity more in AMPK␣ WT than in mdKO muscle. However, analysis of a subgroup of mice matched for running distance revealed that only UQCRC1 protein content increased more in WT than in mdKO mice with exercise training. Thus, AMPK␣1 and -␣2 subunits are important for acute exercise-induced mRNA responses of some genes and may be involved in regulating basal metabolic protein expression but seem to be less important in exercise training-induced adaptations in metabolic proteins.

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“…FA metabolism experiments were conducted in incubation reservoirs (Radnoti, Monrovia, CA) using procedures that have been described previously (29,30). Isolated SOL muscles were incubated at 30°C in Krebs-Henseleit-Ringer buffer, pH 7.4, containing 2 mmol/L pyruvate, 2% FA-free BSA, and 0.5 mmol/L palmitic acid.…”

Section: Fa Oxidationmentioning

confidence: 99%

Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG

et al. 2016

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Type 2 diabetes and skeletal muscle insulin resistance have been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different reactivity in vitro, we investigated whether the described function of DAGs as mediators of lipid-induced insulin resistance was dependent on the different DAG isomers. We measured insulin-stimulated glucose uptake in hormone-sensitive lipase (HSL) knockout (KO) mice after treadmill exercise to stimulate the accumulation of DAGs in skeletal muscle. We found that, despite an increased DAG content in muscle after exercise in HSL KO mice, the HSL KO mice showed a higher insulin-stimulated glucose uptake postexercise compared with wild-type mice. Further analysis of the chemical structure and cellular localization of DAG in skeletal muscle revealed that HSL KO mice accumulated sn-1,3 DAG and not sn-1,2 DAG. Accordingly, these results highlight the importance of taking the chemical structure and cellular localization of DAG into account when evaluating the role of DAG in lipid-induced insulin resistance in skeletal muscle and that the accumulation of sn-1,3 DAG originating from lipolysis does not inhibit insulin-stimulated glucose uptake.

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LKB1 Regulates Lipid Oxidation During Exercise Independently of AMPK

Cited by 69 publications

References 50 publications

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

AMPKα is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle

Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG

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