Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction

Forand, Anne; Koumakis, Eugénie; Rousseau, Alice; Sassier, Yohann; Journé, Clément; Merlin, Jean-François; Leroy, Christine; Boitez, Valérie; Codogno, Patrice; Friedlander, Gérard; Cohen, Isabelle

doi:10.1016/j.celrep.2016.08.012

Cited by 36 publications

(35 citation statements)

References 61 publications

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“…Muscle-specific loss of ERK1/2 was also found to cause loss of neuromuscular integrity in mice 28 , which may contribute to the myopathy in smPit1 −/− ; smPit2 −/− mice. Finally, Pit1 promotes other transport-independent processes such as proliferation 20 and TNF-induced apoptosis in HeLa cells 21 and insulin resistance in hepatocytes 51 . These pathways may be relevant in skeletal muscle as well and may be of interest for further investigation.…”

Section: Discussionmentioning

confidence: 99%

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

Chande

Caballero

et al. 2020

Sci Rep

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Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders. Which Pi transporters are required and whether hormonal changes due to hypophosphatemia contribute to muscle function is unknown. To address these questions we generated a series of conditional knockout mice lacking one or both housekeeping Pi transporters Pit1 and Pit2 in skeletal muscle (sm), using the postnatally expressed human skeletal actin-cre. Simultaneous conditional deletion of both transporters caused skeletal muscle atrophy, resulting in death by postnatal day P13. smPit1 −/− , smPit2 −/− and three allele mutants are fertile and have normal body weights, suggesting a high degree of redundance for the two transporters in skeletal muscle. However, these mice show a gene-dose dependent reduction in running activity also seen in another hypophosphatemic model (Hyp mice). In contrast to Hyp mice, grip strength is preserved. Further evaluation of the mechanism shows reduced ERK1/2 activation and stimulation of AMP kinase in skeletal muscle from smPit1 −/− ; smPit2 −/− mice consistent with energy-stress. Similarly, C2C12 myoblasts show a reduced oxygen consumption rate mediated by Pi transport-dependent and ERK1/2-dependent metabolic Pi sensing pathways. In conclusion, we here show that Pit1 and Pit2 are essential for normal myofiber function and survival, insights which may improve management of hypophosphatemic myopathy. Inorganic phosphate (Pi) is involved in various cellular processes including DNA and cell membrane synthesis, signal transduction, ATP production, and bone mineralization. Serum Pi is regulated by a hormonal bone-parathyroid-kidney axis consisting of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25(OH) 2-D (calcitriol) 1. Familial disorders of Pi homeostasis are caused by mutations in components of this axis that either directly or indirectly (via homeostatic mechanisms) lower serum Pi levels. Furthermore, chronic hypophosphatemia is observed in the often vitamin D-, and therefore Pi-, deficient elderly population 2. How muscle weakness develops in these hypophosphatemic conditions, which Pi transporters are involved and whether the homeostatic hormonal changes, which develop as a result of hypophosphatemia, contribute to reduced muscle function is poorly understood. Previous studies suggest that decreased ATP 3,4 and phosphodiesters 5 may in part explain the muscle weakness seen in hypophosphatemia. We recently reported that hypophosphatemic myopathy goes along with reduced ATP flux (V ATP) and intracellular Pi in an individual with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and in the sodium-Pi co-transporter Npt2a null mouse model of this disorder 6. Basal and insulin-stimulated muscle V ATP and Pi uptake have furthermore been shown to be decreased in the offspring of patients with type 2 diabetes 7 .

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Section: Discussionmentioning

confidence: 99%

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

Chande

Caballero

et al. 2020

Sci Rep

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“…(4) The same set of data was used to demonstrate a role of PiT1 in glucose metabolism independently of its Pi transport function, through its specific interaction with USP7. (9) Finally, Ma and colleagues showed the role of PiT2 in neuronal growth by interacting with MAP1B, independently of its Pi transport function. (10) By interacting with numerous and specific proteins in different organs, the biology of the PiT proteins is much more complex than just being Pi transporters.…”

Section: To the Editormentioning

confidence: 99%

The Need of a Paradigm Shift to Better Understand PiT1 and PiT2 Biology: Response to “Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?”

Beck-Cormier

Beck

2020

Journal of Bone and Mineral Research

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“…In the liver, the dysregulation of USP7 has been observed and used for a prognosis of HCC patients 19 – 21 . A recent finding has linked the regulatory role of USP7 to the hepatic lipid metabolism, showing that USP7 acts as a PiT1-binding partner to regulate hepatic lipogenesis through influence of glucose metabolism 22 . These observations indicate that USP7 probably participates hepatic pathogenesis through mediation of lipogenesis.…”

Section: Introductionmentioning

confidence: 99%

USP7 mediates pathological hepatic de novo lipogenesis through promoting stabilization and transcription of ZNF638

Lin

Bian

et al. 2020

Cell Death Dis

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Aberrant de novo lipogenesis (DNL) results in excessive hepatic lipid accumulation and liver steatosis, the causative factors of many liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). However, the underlying mechanism of DNL dysregulation remains largely unknown. Ubiquitination of proteins in hepatocytes has been shown to be widely involved in lipid metabolism of liver. Here, we revealed that Ubiquitin-specific peptidase 7 (USP7), a deubiquitinase (DUB), played key roles in DNL through regulation of zinc finger protein 638 (ZNF638) in hepatocytes. USP7 has been shown not only to interact with and deubiquitylate ZNF638, but also to facilitate the transcription of ZNF638 via the stabilization of cAMP responsive element binding protein (CREB). USP7/ZNF638 axis selectively increased the cleavage of sterol regulatory element binding protein (SREBP1C) through AKT/mTORC1/S6K signaling, and formed USP7/ZNF638/SREBP1C nuclear complex to regulate lipogenesis-associated enzymes, including acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN), and Stearoyl-CoA desaturase (SCD). In the mice liver steatosis model induced by fructose, USP7 or ZNF638 abrogation significantly ameliorated disease progression. Furthermore, USP7/ZNF638 axis participated in the progression of lipogenesis-associated HCC. Our results have uncovered a novel mechanism of hepatic DNL, which might be beneficial to the development of new therapeutic targets for hepatic lipogenesis-associated diseases.

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Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction

Cited by 36 publications

References 61 publications

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

The Need of a Paradigm Shift to Better Understand PiT1 and PiT2 Biology: Response to “Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?”

USP7 mediates pathological hepatic de novo lipogenesis through promoting stabilization and transcription of ZNF638

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