4.6 Article

LBP Protects Hepatocyte Mitochondrial Function Via the PPAR-CYP4A2 Signaling Pathway in a Rat Sepsis Model

Journal

SHOCK
Volume 56, Issue 6, Pages 1066-1079

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0000000000001808

Keywords

Hepatocyte; LBP; mitochondria; PPAR alpha; sepsis

Funding

  1. National Natural Science Fund of China (NSFC) [81971875]

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The study reveals the protective role of LBP in hepatic mitochondria against LPS-induced damage, potentially through the LBP-PPAR alpha-CYP4a2 signaling pathway.
Objectives: To explore the role of LPS binding protein (LBP) in metabolism and optimize sepsis treatment. Design: A sepsis model was established by injecting LPS into LBP-/- rats and WT rats and observing changes in the liver over time (0, 1, 6, and 24 h). Setting: Detecting liver inflammation and injury. Optimizing the treatment of sepsis. Subjects: WT rats and LBP-/- rats. Interventions: We established a sepsis model by injecting LPS intravenously. Measurements and main results: First, we induced sepsis in WT and LBP-/- rats with LPS. The rats were sacrificed, and serum and liver samples were collected at 1, 6, and 24 h after LPS injection. We found that the deletion of LBP reduced LPS-induced liver inflammation and injury at 1 and 6 h. Ballooning degeneration was clearly present in LBP-/- rat livers at 24 h after LPS injection. We found that mitochondrial damage and reactive oxygen species (ROS) levels were higher in LBP-/- rat livers than in WT rat livers at 24 h after LPS injection. According to the transcriptomic results, the peroxisome proliferator-activated receptor (PPAR) pathway may be the reason for lesions in LBP-/- rats. To further investigate the function of PPAR alpha in sepsis, we inhibited mTOR with rapamycin and examined mitochondrial injury and ROS levels. The levels of mitochondrial damage and ROS were reduced after LBP-/- rats were pretreated with rapamycin in the context of LPS-induced sepsis. Inhibiting CYP4a2, one of the PPAR alpha-target gene products, reduced the level of LPS-induced ROS in LBP-/- rats. Conclusion: LBP protects hepatic mitochondria against LPS-induced damage via the LBP-PPAR alpha-CYP4a2 signaling pathway.

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