Alkaline phosphatase attenuates LPS-induced liver injury by regulating the miR-146a-related inflammatory pathway

https://doi.org/10.1016/j.intimp.2021.108149Get rights and content
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Highlights

  • Oral ALP can attenuate LPS induced inflammation.

  • ALP cannot directly inhibit liver inflammation.

  • ALP attenuates inflammation by regulating mir146a.

  • ALP of raw milk has protective effect on consumers.

Abstract

Lipopolysaccharide (LPS) can remain in dairy products after the sterilization of milk powder and may pose a threat to the health of infants and young children. There is a large amount of alkaline phosphatase (ALP) in raw milk, which can remove the phosphate bond of LPS, thus, detoxifying it. ALP is regarded as an indicator of the success of milk sterilization due to its strong heat resistance. ALP can alleviate the toxicity of LPS in enteritis and nephritis models, but the mechanism by which oral-intake of ALP protects liver tissue from LPS stimulation is unclear. In this study, an in vivo acute mouse liver injury model was induced by C. sakazakii LPS (200 μg/kg) and used to verify the protective mechanism of ALP (200 U/kg) on mice livers. The related pathways were also verified by in vitro cell culture. Enzyme linked immunosorbent assays (ELISAs), quantitative reverse transcription PCR (RT-qPCR) and western blotting were used to detect the levels of inflammatory factors at the protein level and RNA level, and to confirm the inflammation of liver tissue caused by LPS. ALP was found to alleviate acute liver injury in vitro by activating miR-146a. We found that ALP could up-regulate the level of miR146a and subsequently alleviates the expression of TLR4, TNF-α, matured IL-1β, and NF-κB in mouse liver tissue and hepatocytes; thus, reducing liver inflammation. Herein, we demonstrated for the first time that oral-intake of ALP protected liver tissue by up-regulating the expression of miR-146a and alleviating inflammatory reactions; thus, providing a research basis for the proper processing of milk. This study also suggests that producers should improve the awareness of the protective effects of bioactive proteins in raw milk.

Keywords

Lipopolysaccharide
Alkaline phosphatase
Acute liver injury
miR146a
Cronobacter sakazakii

Abbreviations

LPS
Lipopolysaccharide
ALP
Alkaline phosphatase
TLR4
Toll-like receptor 4
TNF-α
Tumor necrosis factor
NF-kB
Nuclear factor-kappa B
IL-1β
Interleukin 1β

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These authors contributed equally to this work.