Medium-Chain Triglycerides Attenuate Liver Injury in Lipopolysaccharide-Challenged Pigs by Inhibiting Necroptotic and Inflammatory Signaling Pathways.

Lin Zhang,Jianglin Xiong,Shaokui Chen,Xiangen Li,Huiling Zhu,Xiuying Wang,Yulan Liu,Zhixiao Tu,Guolong Zhang,Shuhui Wang

doi:10.3390/ijms19113697

Abstract

This study was conducted to investigate whether medium-chain triglycerides (MCTs) attenuated lipopolysaccharide (LPS)-induced liver injury by down-regulating necroptotic and inflammatory signaling pathways. A total of 24 pigs were randomly allotted to four treatments in a 2 × 2 factorial design including diet (0 and 4% MCTs) and immunological challenge (saline and LPS). After three weeks of feeding with or without 4% MCTs, pigs were challenged with saline or LPS. MCTs led to a significant increase in eicosapentaenoic acid, docosahexaenoic acid and total (n-3) polyunsaturated fatty acid concentrations. MCTs attenuated LPS-induced liver injury as indicated by an improvement in liver histomorphology and ultrastructural morphology of hepatocytes, a reduction in serum alanine aminotransferase and alkaline phosphatase activities as well as an increase in claudin-1 protein expression. In addition, MCTs also reduced serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 concentrations, liver TNF-α and IL-1β mRNA expression and protein concentrations and enhanced liver heat shock protein 70 protein expression in LPS-challenged pigs. Moreover, MCTs decreased mRNA expression of receptor-interacting serine/threonine-protein kinase (RIP) 3, mixed-lineage kinase domain-like protein (MLKL) and phosphoglycerate mutase 5 and inhibited MLKL phosphorylation in the liver. Finally, MCTs decreased liver mRNA expression of toll-like receptor (TLR) 4, nucleotide-binding oligomerization domain protein (NOD) 1 and multiple downstream signaling molecules. MCTs also suppressed LPS-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and increased extracellular signal-related kinase 1/2 phosphorylation in the liver. These results indicated that MCTs are capable of attenuating LPS-induced liver damage by suppressing hepatic necroptotic (RIP1/RIP3/MLKL) and inflammatory (TLR4/NOD1/p38 MAPK) signaling pathways.

Highlights

The liver is a vital organ with a wide range of metabolic, detoxification and endocrine functions
This study investigated the hepatoprotective effects and molecular mechanisms of medium-chain triglycerides (MCTs) in a pig model of LPS-induced liver injury
We observed no incorporation of C8–C10 fatty acids into liver lipids but replacement of corn oil with MCTs decreased linoleic acid and total (n-6) polyunsaturated fatty acids (PUFAs) concentrations and the (n-6)/(n-3) ratio

Summary

Introduction

The liver is a vital organ with a wide range of metabolic, detoxification and endocrine functions. The liver is an important immune organ with a unique population of cells that participate in innate and adaptive immune responses [1]. Various bacterial and viral infections, such as acute hepatitis, as well as toxins can result in parenchymal liver injury and dysfunction [2]. Lipopolysaccharide (LPS), a potent endotoxin, plays a critical role in many liver diseases such as alcoholic steatohepatitis [3], nonalcoholic steatohepatitis [4], non-alcoholic fatty liver disease (NAFLD) [4], liver cirrhosis [5] and ischemic liver injury [6]. LPS stimulates liver macrophages (Kupffer cells) to produce various pro-inflammatory cytokines, which leads to inflammatory response and liver injury [7].

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Results

Conclusion