2. Academic Validation
  3. Downregulation of Setdb2 promotes alternative activation of macrophages via the PI3K/Akt pathway to attenuate NAFLD after sleeve gastrectomy

Downregulation of Setdb2 promotes alternative activation of macrophages via the PI3K/Akt pathway to attenuate NAFLD after sleeve gastrectomy

  • Biochem Biophys Res Commun. 2024 Jun 13:726:150264. doi: 10.1016/j.bbrc.2024.150264.
Tianming Yu 1,  Le Wang 2,  Yang Cheng 1,  Yun Zhang 3,  Jiankang Zhu 3,  Guangyong Zhang 4,  Sanyuan Hu 5
Affiliations

Affiliations

  • 1 Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250014, Shandong Province, China.
  • 2 Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
  • 3 Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China; Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University, China; Shandong Engineering Research Center of Diagnosis and Treatment Technology for Bariatric and Metabolism-Associated Surgery, The First Affiliated Hospital of Shandong First Medical University, China.
  • 4 Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China; Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University, China; Shandong Engineering Research Center of Diagnosis and Treatment Technology for Bariatric and Metabolism-Associated Surgery, The First Affiliated Hospital of Shandong First Medical University, China. Electronic address: guangyongzhang@hotmail.com.
  • 5 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China; Diagnosis and Treatment of Bariatric and Metabolism-Associated Surgery, Shandong Provincial Engineering Research Center, China. Electronic address: husanyuan1962@hotmail.com.
PMID: 38905784 DOI: 10.1016/j.bbrc.2024.150264
Abstract

Non-alcoholic fatty liver disease (NAFLD) stands as the most prevalent hepatic disorder, with bariatric surgery emerging as the most effective intervention for NAFLD remission. Sleeve gastrectomy (SG) has notably ascended as the predominant procedure due to its comparative simplicity and consistent surgical outcomes. Nonetheless, the underlying mechanisms remain unclear. In this study, we probed the therapeutic potential of SG for NAFLD induced by a high-fat diet (HFD) in mice, with a focus on its impact on liver lipid accumulation, macrophage polarization, and the role of the Histone Methyltransferase Setdb2. SG prompted significant weight loss, diminished liver size and liver-to-body weight ratio, and enhanced liver function, evidenced by reduced serum levels of triglycerides (TG), total Cholesterol (T-CHO), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological examination confirmed a reduction in liver lipid accumulation. Additionally, flow cytometry unveiled an increased proportion of M2 macrophages and a decrease in Setdb2 expression was shown in the SG group, suggesting an association between Setdb2 levels and postsurgical macrophage polarization. Furthermore, the conditional knockout of Setdb2 in mice further mitigated HFD-induced steatosis and promoted the M2 macrophage phenotype. Mechanistically, Setdb2 knockout in bone marrow-derived macrophages (BMDMs) favored M2 polarization, with RNA sequencing and western blotting analyses corroborating the upregulation of the PI3K/Akt signaling pathway. The effects of Setdb2 on macrophage activation were nullified by the PI3K Inhibitor LY294002, suggesting that Setdb2 facilitates alternative macrophage activation through the PI3K/Akt signaling pathway. These comprehensive findings underscore the potential of SG as a therapeutic intervention for NAFLD by regulating the critical function of Setdb2 in macrophage polarization and activation, thereby offering novel insights into NAFLD pathogenesis and therapeutic targets.

Keywords

Macrophage polarization; Non-alcoholic fatty liver disease; PI3K-Akt signaling pathway; Setdb2; Sleeve gastrectomy.

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