Contribution and mechanism study of HSPA12A on liver injury during endotoxemia
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Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University

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Youth Program of Natural Science Foundation of Jiangsu Province

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    Abstract:

    [Abstract] Objective: To explore the effects and mechanisms of heat shock protein A12A (HSPA12A) on liver injury during endotoxemia. Methods: (1) Bioinformatic analysis of mRNA expression changes in the expression of Hspa12a and multiple apolipoprotein using a public database of septic mouse liver tissue RNA sequencing. (2) Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS) (5 mg/kg) using 6-8-week-old HSPA12A knockout (Hspa12a-/-) mice and wild-type (WT) mice. Mice treated with normal saline (NS) served as controls. Expertiments were divided into four groups, NS-WT group, NS-Hspa12a-/- group, LPS-WT group and LPS-Hspa12a-/- group. Six hours after LPS, liver tissues were collected for examing tissue damage by HE and analyzing the expression levels of HSPA12A, APOA1, APOB, and APOM by immunoblotting and RT-PCR. At the same time, serum was separated for measuring levels of liver function markers (alanine aminotransferase, ALT; aspartate aminotransferase, AST) and lipoproteins( high density lipoprotein cholesterol, HDL-C; low density lipoprotein cholesterol, LDL-C). (3) Primary hepatocytes were treated with LPS (500 ng/ml) after HSPA12A overexpressed to emulate endotoxemia induced liver injury. Six hours after LPS, medium was collected for measuring levels of ALT and AST. (4) Patients were divided into sepsis induced liver injury group and control group according to whether the liver injury occurred. ALT, AST, HDL-C and LDL-C levels of patients were collected for analyse. Results: (1) Bioinformatics analysis showed decreases of Hspa12a, Apoa1, Apob and Apom mRNA levels in livers during sepsis. (2) LPS-WT mice displayed a decrease in HSPA12A (P<0.05) protein expression in livers along with the elevated serum ALT (P<0.05) and AST (P<0.01) activiaties compared with NS-WT mice. At the same time, liver tissues showed obvious histopathological injury (P<0.001) and the number of inflammatory foci was decreased (P<0.01). However, compare to LPS-WT mice, LPS- Hspa12a-/- group showed greater ALT (P<0.01) and AST (P<0.05) levels and lower HDL-C and LDL-C levels (P<0.01), along with more severe pathological damage of liver tissues (P<0.05), suggesting that HSPA12A deficiency exaggerated liver injury during endotoxemia. Hepatic apolipoproteins (APOA1, APOB, APOM) expression was reduced (P<0.05, P<0.01). (3) In vitro, ALT and AST levels in culture medium of hepatocytes were signaficantly increased after LPS treatment (P<0.001). However, overexpression of HSPA12A could alleviate the increases of ALT and AST levels (P<0.01). (4) Clinical results suggested that compared with control group, sepsis induced liver injury group shows signaficantly higher ALT and AST levels in serum (P<0.001). In contrast, HDL-C and LDL-C levels were signaficantly lower (P<0.001). Conclusions: Endotoxemia leads to downregulation of hepatic HSPA12A expression, ewhich mediates the development of endotoxemic liver injury. However, overexpression of HSPA12A can protect liver injury induced by endotoxemia. The action of HSPA12A may involve the regulation of hepatic apolipoprotein expression and serum lipoprotein cholesterol levels.

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History
  • Received:December 21,2023
  • Revised:March 28,2024
  • Adopted:May 07,2024
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