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Multicomponent Parenteral Lipid Emulsions Do Not Protect Against Liver Injury in Neonatal Pigs with Obstructive Cholestasis

ABSTRACT: Multicomponent Parenteral Lipid Emulsions Do Not Protect Against Liver Injury in Neonatal Pigs with Obstructive Cholestasis

PROVIDER: PRJNA1184760 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR31307341_1.fastq.gz	Fastqsanger.gz
	SRR31307341_2.fastq.gz	Fastqsanger.gz
	SRR31307342_1.fastq.gz	Fastqsanger.gz
	SRR31307342_2.fastq.gz	Fastqsanger.gz

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Project description:Background: Vitamin A is an essential nutrient that mammals obtain from dietary carotenoids and retinyl esters. Bile salts aid in the intestinal absorption of vitamin A, after which it is stored in the stellate cells of the liver. Vitamin A-metabolites, such as retinoic acids, are important for cell differentiation, proliferation and immunological processes, and act mostly by activating the nuclear receptors Retinoic Acid Receptor (RAR) and Retinoid Xreceptor (RXR). These receptors also perform key functions in the liver by regulating bile salt, lipid and glucose homeostasisas well is the intrahepatic immune response. Chronic liver diseases are characterized by hepatic vitamin A loss often leading to vitamin A deficiency (VAD). We found that VAD strongly aggravates liver damage in bile duct ligated (BDL) rats and in biliary atresia patients. Here, we performed a transcriptome analysis to characterize the cell biological processes in the rat liver that are disturbed in obstructive cholestasis under VADconditions. Methods: Rats were made VAD by omitting vitamin A from the diet for 16 weeks, followed by ligation of the common bile duct (BDL). 7 days later, the animals were sacrificed. During the 7 days of BDL, half of the animals received daily IP injections with retinyl-palmitate (vitamin A therapy). Bile salt concentrations and liver damage markers (AST/ALT) were determined in serum. Whole genome gene expression in liver tissue was analyzed with the Illumina platform RatRef-12 beadchip. False discovery rate (FDR) was set at a stringent 1%. Data were confirmed by quantitative real time PCR, Western blotting and/or histochemistry. Results: BDL induced dramatic liver damage in VAD rats with serum liver damage markers (AST/ALT)approximately 10-fold increased compared to BDL rats receiving a vitamin A-sufficient (VAS) diet. Only 20 genes were differentially expressed between sham-treated VAS and VAD rats and clustered in the vitamin A metabolism, immune response, carbohydrate and lipid homeostasis. In contrast, 1583 genes were differentially expressed between the BDL-treated VAS and VAD rats. The strongest effects were observed in genes from the vitamin A metabolism, immune response, collagen production and oxidative stress response. Importantly, all the liver damage markers were efficiently reversed by retinyl-palmitate therapy, which was mirrored by an almost complete normalisation of the transcript profile in VAS-BDL rats. Conclusions: We conclude that vitamin A deficiency dramatically aggravates liver damage caused by obstructive cholestasis. The transcriptome analysis suggests that a disturbed immune response may be the predominant causative factor.

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Multicomponent Parenteral Lipid Emulsions Do Not Protect Against Liver Injury in Neonatal Pigs with Obstructive Cholestasis

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