Author Correction: Lkb1 suppresses amino acid-driven gluconeogenesis in the liver (original) (raw)
Related papers
Lkb1 suppresses amino acid-driven gluconeogenesis in the liver
Nature Communications
Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
Nature Communications, 2014
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liverspecific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.
LKB1 loss of function studied in vivo
FEBS letters, 2011
Recent developments have placed the serine/threonine kinase LKB1 on the crossroads linking energy metabolism, cell structure and cancer progression and that its deletion can affect tumorigenesis, metastasis, cell adhesion and polarity. LKB1 can regulate a host of different functions which all have potential to impact upon the initiation and progression of neoplastic disease. To understand the phenotypic consequences of LKB1 loss in a range of different settings, a number of animal models of loss of function have been generated and analyzed. In this review we summarize recent data generated from a range of these models, which reveal clear tissue specific differences in LKB1 function in vivo and in the consequences of its loss.
2014
Abstract: Liver kinase B1 (LKB1), known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK)-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK), salt-inducible kinase (SIK), sucrose non-fermenting protein-related kinase (SNRK) and brain selective kinase (BRSK) signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understan...
International journal of molecular sciences, 2014
Liver kinase B1 (LKB1), known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK)-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK), salt-inducible kinase (SIK), sucrose non-fermenting protein-related kinase (SNRK) and brain selective kinase (BRSK) signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of th...
The Tumor Suppressor Kinase LKB1: Metabolic Nexus
Frontiers in Cell and Developmental Biology, 2022
Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.
Hepatology Communications
Liver kinase B 1 (LKB1 or STK11) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) are two tumor suppressors that regulate the mammalian target of rapamycin signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb 1/-) or Pten (Pten loxP/loxP ; Alb-Cre 1) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show that haplo-insufficiency of Lkb1 in the liver leads to advanced tumor development in Pten-null mice (Pten loxP/loxP ; Lkb loxP/1 ; Alb-Cre 1). Our analysis shows that LKB1 and PTEN interact with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN (Pten loxP/loxP ; Lkb loxP/loxP ; Alb-Cre 1) also leads to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase, indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein multidrug resistant protein 2, which is responsible for clearing bilirubin. This observed regulation of multidrug resistant protein 2 by LKB1 likely contributes to the lack of cellular polarity and the early lethality phenotype associated with the homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1-deleted livers. Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidated key molecular targets for such interactions.
Diabetologia, 2012
Aims/hypothesis Protein kinase Cε (PKCε) is emerging as a key mediator of lipid-induced insulin resistance in liver and hepatic lipid metabolism itself. We investigated whether PKCε plays a role in other metabolic processes, to further examine its suitability as a therapeutic target. Methods We measured amino acid, organic acid and sugar levels by liquid and gas chromatography-mass spectrometry of liver extracts from chow and fat-fed wild-type Keywords Alanine. Gluconeogenesis. β-Hydroxybutyrate. Ketone. Liver. Metabolomics. Protein kinase C Abbreviations βHB β-Hydroxybutyrate LC-MS Liquid chromatography-MS PKCε Protein kinase Cε WT Wild type Electronic supplementary material The online version of this article