Abstract

The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been debated in recent decades. Here, we established an intestinal barrier dysfunction model in mice and Caco2 cell line by Lipopolysaccharide (LPS), and evaluated the fatty acid uptake capacity of the intestine. We found that LPS stimulation restricted the absorption of long chain fatty acid (LCFA), while Cathelicidin-WA (CWA) pretreatment facilitated this physiological process. At the molecular level, our results demonstrated that the stimulatory effects of CWA on intestinal lipid absorption were dependent on cluster determinant 36 and fatty acid transport protein 4, but not fatty acid–binding protein. Further, an enhanced intestinal barrier was observed in vivo and in vitro when CWA alleviated the fatty acid absorption disorder induced by LPS stimulation. Mechanistically, peroxisome proliferator-activated receptor (PPAR-γ) signaling was considered as a key pathway for CWA to enhance LCFA absorption and barrier function. Treatment with a PPAR-γ inhibitor led to impaired intestinal barrier function and suppressed LCFA uptake. Moreover, once PPAR-γ signaling was blocked, CWA pretreatment could not maintain the stability of the intestinal epithelial cell barrier or LCFA uptake after LPS stimulation. Collectively, these findings suggested that PPAR-γ may serve as a target for specific therapies aimed at alleviating fatty acid uptake disorder, and CWA showed considerable potential as a new PPAR-γ agonist to strengthen intestinal barrier function against fatty acid malabsorption.

Highlights

  • Long-chain fatty acids (LCFAs, FAs with 12–18 carbons and varying degrees of unsaturation), stored as triglycerides in the body, serve several important functions in the human body [1]

  • GW9662 and Rosiglitazone were obtained from Target Molecule (Shanghai, China).The rabbit antibodies for β-actin, zonula occludens (ZO)-1, cluster determinant 36 (CD36), FATP4, I-fatty acid–binding proteins (FABP), peroxisome proliferator activated receptor (PPAR)-γ were purchased from Proteintech (Wuhan, China)

  • These results indicated that LPS restricted long chain fatty acid (LCFA) absorption in the intestine, while CWA pretreatment restored the absorptive process during LPS stimulation

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Summary

Introduction

Long-chain fatty acids (LCFAs, FAs with 12–18 carbons and varying degrees of unsaturation), stored as triglycerides in the body, serve several important functions in the human body [1]. Dietary LCFAs are the only source of essential fatty acids that serve as substrates for lipid biosynthesis, and protein modification [1]. Because of the metabolic syndrome is related to cardiovascular disease, obesity, diabetes, and cancer, many studies have focused mainly on identifying cellular, physical/chemical, and genetic determinants of intestinal fatty acid absorption in humans and laboratory animals [6]. It is generally known that before cholesterol and fatty acid molecules can interact with their corresponding transporters for uptake and absorption, they must pass through a diffusion barrier [7, 8]. Wang et al [7] found that epithelial mucin was necessary for normal intestinal uptake and absorption of cholesterol in mice, as evidenced by a 50% reduction in cholesterol absorption efficiency in mucin knockout mice

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