Dataset Information

LKB1 is a suppressor of amino acid-driven gluconeogenesis in the liver

ABSTRACT: Excessive hepatic glucose production is a major contributor to the hyperglycemia observed in Type 2 diabetes mellitus. It is widely accepted that it is due to an increase in hepatic gluconeogenesis. While much attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, much less is known about the regulation of amino acid catabolism that provides gluconeogenic substrates. Here, we emphasize a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have increased hepatic amino acid catabolism for gluconeogenesis. This occurred during fasting, as well as during the postprandial period, identifying Lkb1 as a critical suppressor of hepatic postprandial gluconeogenesis. Hepatic Lkb1 deletion was also associated with severe alterations in whole body metabolism leading to decreased lean body mass deposition on MRI analysis and, at a longer term, cachexia and sarcopenia as a consequence of the diversion of amino acids for liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and Agxt and as critical effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: François GUILLONNEAU

LAB HEAD: Dr Christine Perret

PROVIDER: PXD013478 | Pride | 2020-12-01

REPOSITORIES: Pride

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Publications

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver.

Just Pierre-Alexandre PA Charawi Sara S Denis Raphaël G P RGP Savall Mathilde M Traore Massiré M Foretz Marc M Bastu Sultan S Magassa Salimata S Senni Nadia N Sohier Pierre P Wursmer Maud M Vasseur-Cognet Mireille M Schmitt Alain A Le Gall Morgane M Leduc Marjorie M Guillonneau François F De Bandt Jean-Pascal JP Mayeux Patrick P Romagnolo Béatrice B Luquet Serge S Bossard Pascale P Perret Christine C

Nature communications 20201130 1

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. He ...[more]

PMID: 33257663

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Project description:Background: While the mechanisms underlying the lactation-induced adaptations of intermediary metabolism and immune response have been extensively studied in rodents and dairy cows, little is known in this regard in sows. Therefore, the present study aimed to explore the lactation-induced changes in hepatic gene expression in sows during lactation. Results: Using a porcine whole-genome microarray a total of 632 differentially expressed genes in the liver of lactating compared to non-lactating sows (each n = 10) could be identified. Enrichment analysis revealed that the differentially expressed genes were mainly involved in fatty acid metabolism, pyruvate metabolism, glutathione metabolism, glycine, serine and threonine metabolism, citrate cycle, glycerophospholipid metabolism, PPAR signaling, nitrogen metabolism, and focal adhesion. The most striking observation with respect to intermediary metabolism was that genes involved in fatty acid catabolism, the catabolism of gluconeogenic amino acids, the citrate cycle and the respiratory chain were up-regulated in the liver of sows during lactation. With respect to immune response, it could be demonstrated that genes encoding acute phase proteins and genes involved in tissue repair were up-regulated and genes encoding focal adhesion molecules were down-regulated in the liver of sows during lactation. Conclusion: The results from this study indicate that energy-generating pathways and pathways involved in the delivery of gluconeogenic substrates are induced in the liver of sows during lactation. The alterations of expression of genes encoding proteins involved in immune response suggest that lactation in sows may cause an adaptive immune response which possibly counteracts hepatic inflammation. For microarray analyses, four RNA pools each, for the non-lactating group (n = 4) and the lactating group (n = 4), were prepared from eight individual sows per group. To each RNA pool, RNA from two different sows per group contributed identical amounts of RNA.

Dataset Information

LKB1 is a suppressor of amino acid-driven gluconeogenesis in the liver

Publications

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver.

Similar Datasets

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