{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:10:50Z","timestamp":1786133450805,"version":"build-2736575974"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,6]]},"abstract":"\n Significance Statement<\/jats:title>\n Lipolysis is of particular importance for energy homeostasis in proximal tubular epithelial cells (PTECs), and it is dysregulated during the pathogenesis of diabetic kidney disease. In knockout mice lacking O-GlcNAc transferase specifically in PTECs, the authors demonstrated that protein O-GlcNAcylation, an intracellular nutrient sensing system, is essential for renal lipolysis and ATP production during prolonged fasting. They also found evidence that this novel regulatory mechanism of renal lipolysis involves farnesoid X receptor\u2013dependent upregulation of carboxylesterase-1 and that deficiency of renal protein O-GlcNAcylation exacerbates tubulopathy in diabetic kidney disease. These findings suggest that manipulation of the renal lipolytic mechanism to overcome the effects of prolonged fasting might represent a novel therapeutic approach for diabetic kidney disease.<\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To investigate the mechanism of renal lipolysis in PTECs\u2014specifically, the role played by protein O-GlcNAcylation\u2014we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during\n ad libitum<\/jats:italic>\n feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during\n ad libitum<\/jats:italic>\n feeding, after fasting 48 hours, they developed Fanconi syndrome\u2013like abnormalities, PTEC apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor\u2013dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation\u2019s 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018090950","type":"journal-article","created":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T20:35:22Z","timestamp":1556742922000},"page":"962-978","source":"Crossref","is-referenced-by-count":27,"title":["Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes"],"prefix":"10.1681","volume":"30","author":[{"given":"Sho","family":"Sugahara","sequence":"first","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Kume","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Chin-Kanasaki","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"},{"name":"Division of Blood Purification, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issei","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mako","family":"Yasuda-Yamahara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Yamahara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihisa","family":"Osawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Yanagita","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Araki","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"},{"name":"Division of Blood Purification, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Maegawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,5,1]]},"reference":[{"key":"B1-20230929","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/ki.1976.26","article-title":"Sites of enzyme activity along the nephron.","volume":"9","author":"Schmidt","year":"1976","journal-title":"Kidney Int"},{"key":"B2-20230929","first-page":"F407","article-title":"Metabolic substrate utilization by rabbit proximal tubule. 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