Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling

Javary, Joaquim; Allain-Courtois, Nathalie; Saucisse, Nicolas; Costet, Pierre; Heraud, Capucine; Benhamed, Fadila; Pierre, Rémi; Buré, Corinne; Pallares-Lupon, Néstor; Cruzeiro, Marcio Do; Postic, Catherine; Cota, Daniela; Dubus, Pierre; Rosenbaum, Jean; Benhamouche-Trouillet, Samira

doi:10.1136/gutjnl-2017-314208

Cited by 19 publications

(29 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data led us to conclude that PGC-1–induced changes in mRNA noted for mTOR pathway members (Fig. 2) were likely due to indirect feedback on this arm of the pathway, as seen previously (16), and not due to direct coactivation by the PGC-1s. PGC1B, while having the same ability as PGC1A to decrease IRS1 protein, did not increase IRS2 (Fig.…”

Section: Resultssupporting

confidence: 80%

PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

Besse-Patin

Jeromson

Levesque-Damphousse

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

show abstract

Section: Resultssupporting

confidence: 80%

PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

Besse-Patin

Jeromson

Levesque-Damphousse

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…During the drafting of this article, we became aware of a report on opposite mTORC1 and mTORC2 regulation by hepatic RuvBL2/Reptin. 35 Despite the fact that depletion of RuvBL2 affects mTOR protein levels, similarly to what we observe with RuvBL1, Reptin LIKO mice showed an improved glucose metabolism and reduced gluconeogenesis on chow and HFD diet. Loss of mTOR expression in these mice affected mTORC1 function while enhancing mTORC2 activity.…”

Section: Discussionsupporting

confidence: 66%

Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression

Mello

Materozzi

Zanieri

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

RuvBL1 is an AAA+ ATPase whose expression in hepatocellular carcinoma (HCC) correlates with a poor prognosis. In vitro models suggest that targeting RuvBL1 could be an effective strategy against HCC. However, the role of RuvBL1 in the onset and progression of HCC remains unknown. To address this question, we developed a RuvBL1 hep+/− mouse model and evaluated the outcome of DEN-induced liver carcinogenesis up to 12 months of progression. We found that RuvBL1 haploinsufficiency initially delayed the onset of liver cancer, due to a reduced hepatocyte turnover in RuvBL1 hep+/− mice. However, RuvBL1 hep+/− mice eventually developed HCC nodules that, with aging, grew larger than in the control mice. Moreover, RuvBL1 hep+/− mice developed hepatic insulin resistance and impaired glucose homeostasis. We could determine that RuvBL1 regulates insulin signaling through the Akt/mTOR pathway in liver physiology in vivo as well as in normal hepatocytic and HCC cells in vitro. Whole transcriptome analysis of mice livers confirmed the major role of RuvBL1 in the regulation of hepatic glucose metabolism. Finally, RuvBL1 expression was found significantly correlated to glucose metabolism and mTOR signaling by bioinformatic analysis of human HCC sample from the publicly available TGCA database. These data uncover a role of RuvBL1 at the intersection of liver metabolism, hepatocyte proliferation and HCC development, providing a molecular rationale for its overexpression in liver cancer.M.M. and F.Z. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

show abstract

“…Liver-specific ablation of Reptin strongly inhibits hepatic mTORC1 activity, leading to significant decrease in de novo lipogenesis and cholesterol production. Meanwhile, mTORC2 activity is greatly enhanced and hepatic glucose production is inhibited [ 39 ].…”

Section: Mtor Signaling In Livermentioning

confidence: 99%

Role of mTOR in Glucose and Lipid Metabolism

Mao

Zhang

2018

IJMS

204

170

View full text Add to dashboard Cite

The mammalian target of rapamycin, mTOR is the master regulator of a cell’s growth and metabolic state in response to nutrients, growth factors and many extracellular cues. Its dysregulation leads to a number of metabolic pathological conditions, including obesity and type 2 diabetes. Here, we review recent findings on the role of mTOR in major metabolic organs, such as adipose tissues, liver, muscle, pancreas and brain. And their potentials as the mTOR related pharmacological targets will be also discussed.

show abstract

Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling

Abstract: We show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.

Cited by 19 publications

References 49 publications

PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression

Role of mTOR in Glucose and Lipid Metabolism

Contact Info

Product

Resources

About