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  2. Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes

Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes

  • J Am Soc Nephrol. 2019 Jun;30(6):962-978. doi: 10.1681/ASN.2018090950.
Sho Sugahara 1 Shinji Kume 2 Masami Chin-Kanasaki 1 3 Issei Tomita 1 Mako Yasuda-Yamahara 1 Kosuke Yamahara 1 Naoko Takeda 1 Norihisa Osawa 1 Motoko Yanagita 4 Shin-Ichi Araki 1 3 Hiroshi Maegawa 2
Affiliations

Affiliations

  • 1 Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
  • 2 Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan; [email protected] [email protected].
  • 3 Division of Blood Purification, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan; and.
  • 4 Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract

Background: Energy metabolism in proximal tubular epithelial cells (PTECs) is unique, because ATP production largely depends on lipolysis in both the fed and fasting states. Furthermore, disruption of renal lipolysis is involved in the pathogenesis of diabetic tubulopathy. Emerging evidence suggests that protein O-GlcNAcylation, an intracellular nutrient-sensing system, may regulate a number of metabolic pathways according to changes in nutritional status. Although O-GlcNAcylation in PTECs has been demonstrated experimentally, its precise role in lipolysis in PTECs is unclear.

Methods: To investigate the mechanism of renal lipolysis in PTECs-specifically, the role played by protein O-GlcNAcylation-we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during ad libitum feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes.

Results: Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during ad libitum feeding, after fasting 48 hours, they developed Fanconi syndrome-like abnormalities, PTEC Apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor-dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation's regulation of lipolysis in fasted PTECs. PTEC-specific Ogt-deficient mice with diabetes induced by a high-fat diet developed severe tubular cell damage and enhanced lipotoxicity.

Conclusions: Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.

Keywords

diabetes mellitus; lipids; obesity; renal proximal tubule cell.

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