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. 2023 Dec;61(1):306-315.
doi: 10.1080/13880209.2023.2168018.

Protective effect of omega-3 polyunsaturated fatty acids on sepsis via the AMPK/mTOR pathway

Peng Liu  1 , Ming Li  1 , Wei Wu  1 , Anjie Liu  2 , Honglin Hu  1 , Qin Liu  1 , Chengzhi Yi  1
Affiliations

Protective effect of omega-3 polyunsaturated fatty acids on sepsis via the AMPK/mTOR pathway

Peng Liu et al. Pharm Biol. 2023 Dec.

Abstract

Context: Sepsis is a systemic inflammatory response caused by infection, with high morbidity and mortality. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have reported biological activities.

Objective: This study explored the signaling pathways through which ω-3 PUFAs protect against sepsis-induced multiorgan failure.

Materials and methods: Septic Sprague-Dawley (SD) rat model was established by the cecum ligation perforation (CLP) method. Rats were divided into control, sham, model, parenteral ω-3 PUFAs (0.5 g/kg) treatment, ω-3 PUFAs (0.5 g/kg) + AMPK inhibitor Compound C (30 mg/kg) treatment, and ω-3 PUFAs (0.5 g/kg) + mTOR activator MHY1485 (10 mg/kg) treatment groups. The serum inflammatory cytokines were measured using ELISA. Organ damage-related markers cTnI, CK, CK-MB, Cr, BUN, ALT, and AST were measured using an automated chemical analyzer. The AMPK/mTOR pathway in liver, kidney, and myocardial tissues was detected using western blot and qRT-PCR methods.

Results: CLP treatment enhanced the secretion of pro-inflammatory cytokines and multi-organ related markers, along with increased p-AMPK/AMPK ratio (from 0.47 to 0.87) and decreased p-mTOR/mTOR ratio (from 0.33 to 0.12) in rats. The inflammation response and multi-organ injury induced by CLP treatment could be partially counteracted by 0.5 g/kg parenteral ω-3 PUFA treatment. The activated AMPK/mTOR pathway in CLP-induced rats was further promoted. Finally, Compound C and MHY1485 could reverse the effects of parenteral ω-3 PUFA treatment on sepsis rats.

Discussion and conclusion: ω-3 PUFAs ameliorated sepsis development by activating the AMPK/mTOR pathway, serving as a potent therapeutic agent for sepsis. Further in vivo studies may validate potential clinical use.

Keywords: Cecum ligation perforation; inflammation; organ injury.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Secretion of inflammatory cytokines in blood samples from rats administered with CLP. (A) IL-1β; (B) TNF-α; (C) IL-6; (D) IL-10; (E) IFN-γ; (F) IL-17. **p < 0.01 vs. Sham; ##p < 0.01 vs. Model.
Figure 2.
Figure 2.
Levels of organ damage-related markers in rats after LPS challenge. (A) cTnI; (B) CK; (C) CK-MB; (D) BUN; (E) Cr; (F) ALT; (G) AST. CTnI, cardiac troponin I; CK, creatine kinase; CK-MB, creatine kinase-MB; Cr, creatinine; BUN, blood urea nitrogen; ALT, alanine transaminase; AST, aspartate transaminase. **p < 0.01 vs. Sham; ##p < 0.01 vs. Model.
Figure 3.
Figure 3.
AMPK/mTOR pathway in cardiac muscle tissues from CLP-treated rats. (A) Protein expressions of AMPK, p-AMPK, mTOR and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Sham; ##p < 0.01 vs. Model.
Figure 4.
Figure 4.
AMPK/mTOR pathway in kidney tissues from CLP-treated rats. (A) Protein expression of AMPK, p-AMPK, mTOR, and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Sham; ##p < 0.01 vs. Model.
Figure 5.
Figure 5.
AMPK/mTOR pathway in liver tissues from CLP-treated rats. (A) Protein expression of AMPK, p-AMPK, mTOR and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Sham; ##p < 0.01 vs. Model.
Figure 6.
Figure 6.
Secretion of inflammatory cytokines in blood samples from rats after treatment. (A) IL-1β; (B) TNF-α; (C) IL-6; (D) IL-10; (E) IFN-γ; (F) IL-17. **p < 0.01 vs. Model; ##p < 0.01 vs. Model + ω-3 PUFAs.
Figure 7.
Figure 7.
Levels of organ damage-related markers in rats with sepsis after treatment. (A) cTnI; (B) CK; (C) CK-MB; (D) Cr; (E) BUN; (F) ALT; (G) AST. CTnI, cardiac troponin I; CK, creatine kinase; CK-MB, creatine kinase-MB; Cr, creatinine; BUN, blood urea nitrogen; ALT, alanine transaminase; AST, aspartate transaminase. **p < 0.01 vs. Model; ##p < 0.01 vs. Model + ω-3 PUFAs.
Figure 8.
Figure 8.
AMPK/mTOR pathway in cardiac muscle tissues from CLP-treated rats. (A) Protein expression of AMPK, p-AMPK, mTOR and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Model; ##p < 0.01 vs. Model + ω-3 PUFAs.
Figure 9.
Figure 9.
AMPK/mTOR pathway in kidney tissues from CLP-treated rats. (A) Protein expression of AMPK, p-AMPK, mTOR and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Model; ##p < 0.01 vs. Model + ω-3 PUFAs.
Figure 10.
Figure 10.
AMPK/mTOR pathway in liver tissues from CLP-treated rats. (A) Protein expression of AMPK, p-AMPK, mTOR, and p-mTOR. (B) Quantified results of p-AMPK. (C) Quantified results of p-mTOR. (D and E) mRNA levels of AMPK and mTOR evaluated using qRT-PCR. **p < 0.01 vs. Model; ##p < 0.01 vs. Model + ω-3 PUFAs.
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