2. Academic Validation
  3. 3-Hydroxybutyrate ameliorates sepsis-associated acute lung injury by promoting autophagy through the activation of GPR109α in macrophages

3-Hydroxybutyrate ameliorates sepsis-associated acute lung injury by promoting autophagy through the activation of GPR109α in macrophages

  • Biochem Pharmacol. 2023 May 30;115632. doi: 10.1016/j.bcp.2023.115632.
Mingxin Huang 1,  Yiqin Yu 1,  Xuheng Tang 1,  Rui Dong 1,  Xiaojie Li 1,  Fen Li 1,  Yongxin Jin 1,  Shenhai Gong 2,  Xingmin Wang 3,  Zhenhua Zeng 4,  Lin Huang 5,  Hong Yang 6
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China, 510665; The Third Clinical College of Southern Medical University, Guangzhou, China, 510665.
  • 2 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China, 510515.
  • 3 Department of Pathology, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China, 545001.
  • 4 Department of Critical Care Medicine, Nanfang Hospital of Southern Medical University, Southern Medical University, Guangzhou, China, 510515.
  • 5 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China, 510665; The Third Clinical College of Southern Medical University, Guangzhou, China, 510665. Electronic address: [email protected].
  • 6 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China, 510665; The Third Clinical College of Southern Medical University, Guangzhou, China, 510665; Department of Critical Care Medicine, Nanfang Hospital of Southern Medical University, Southern Medical University, Guangzhou, China, 510515; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, China, 510515. Electronic address: [email protected].
PMID: 37263300 DOI: 10.1016/j.bcp.2023.115632
Abstract

Background: Sepsis is a systemic inflammatory disease caused by multiple pathogens, with the most commonly affected organ being the lung. 3-hydroxybutyrate plays a protective role in inflammatory diseases through Autophagy promotion; however, the exact mechanism remains unexplored.

Method: Our study used the MIMIC-III database to construct a cohort of ICU sepsis patients and figure out the correlation between the level of ketone bodies and clinical prognosis in septic patients. In vivo and in vitro models of sepsis were used to reveal the role and mechanism of 3-hydroxybutyrate in sepsis-associated acute lung injury (sepsis-associated ALI).

Result: Herein, we observed a strong correlation between the levels of ketone bodies and clinical prognosis in patients with sepsis identified using the MIMIC- III database. In addition, exogenous 3-hydroxybutyrate supplementation improved the survival rate of CLP-induced sepsis in mice by promoting Autophagy. Furthermore, 3-hydroxybutyrate treatment protected against sepsis-induced lung damage. We explored the mechanism underlying these effects. The results indicated that 3-hydroxybutyrate upregulates Autophagy levels by promoting the transfer of transcription factor EB (TFEB) to the macrophage nucleus in a G-protein-coupled receptor 109 alpha (GPR109α) dependent manner, upregulating the transcriptional level of ultraviolet radiation resistant associated gene (UVRAG) and increasing the formation of autophagic lysosomes.

Conclusion: 3-hydroxybutyrate can serve as a beneficial therapy for sepsis-associated ALI through the upregulation of Autophagy. These results may provide a basis for the development of promising therapeutic strategies for sepsis-associated ALI.

Keywords

3-Hydroxybutyrate; G-protein-coupled receptor 109α; autophagy; macrophage; sepsis-associated acute lung injury; transcription factor EB.

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