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Abstract: TH-PO532

PPARα in Proximal Tubules Maintains Systemic Energy Homeostasis During Starvation

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Aomura, Daiki, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Nimura, Takayuki, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Yamada, Yosuke, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Harada, Makoto, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Hashimoto, Koji, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
  • Yanagita, Motoko, Kyoto Daigaku Igakubu Fuzoku Byoin, Kyoto, Japan
  • Kamijo, Yuji, Shinshu Daigaku Igakubu Fuzoku Byoin, Matsumoto, Nagano, Japan
Background

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear transcription factor mainly expressed in the liver and renal proximal tubules (PTs). PPARα is especially activated under energy deficient conditions, such as starvation and severe organ injury, to maintain tissue energy homeostasis by accelerating fatty acid oxidation (FAO). Although earlier research has studied the importance of systemic PPARα in the homeostasis of renal energy metabolism, the role of renal PPARα remains unknown. The present study assessed this issue using PT-specific PPARα knock-out mice under fasting conditions.

Methods

Ppara flox/flox mice were bred with Ndrg1-CreERT2 transgenic mice to generate Ndrg1-CreERT2-Ppara flox/flox mice (PTs-PPARα-CKO). PT-specific defects in PPARα expression after 3 days of tamoxifen injection was then confirmed in the PTs-PPARα-CKO mice by quantitative PCR and immunohistochemical staining. To assess the role of PPARα in PTs, tamoxifen-treated 13-week-old Ppara flox/flox mice (controls) and PTs-PPARα-CKO mice were fasted for 0, 24, and 48 hours (n=5-7 in each group).

Results

Without fasting, the renal gene expressions related to FAO and ketogenesis were significantly lower in the PTs-PPARα-CKO mice. Although observed phenotypes were similar between the groups, blood glucose level was slightly but significantly lower in the PTs-PPARα-CKO animals. Under fasting conditions, the renal gene expressions concerning PPARα, FAO, and ketogenesis were dramatically increased in controls, which was not seen in the knock-out mice. The decrease in blood glucose level with fasting was significantly more severe for PTs-PPARα-CKO. Moreover, the hepatic gene expressions related to glycogenolysis, gluconeogenesis, PPARα, FAO, and ketogenesis were all significantly more increased in PTs-PPARα-CKO mice.

Conclusion

Our results demonstrated that PTs-PPARα-CKO mice were prone to hypoglycemia upon starvation. PPARα in PTs may play a role in the homeostasis of serum glucose level and systemic energy metabolism.