Intestinal Hur Deficiency Exacerbates Diet-Induced Fatty Liver Disease

Background Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. However, no effective treatment is available due to the limited knowledge regarding the complex disease pathology. We and others have previously reported that impaired intestinal barrier function promotes the progression of various liver diseases, including NAFLD. Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins. It is reported that HuR is essential for maintaining gut epithelial integrity, and targeted deletion of HuR in the intestinal epithelium disrupts mucosal regeneration in mice. However, the role of intestinal HuR in NAFLD remains unclear and is the focus of this study. Methods: Intestinal epithelial tissue-specific HuR deletion (IE-HuR–/–) mice were generated by crossing the HuRflox/flox (HuRfl/fl) and villin-Cre mice. Age and gender-matched IE-HuR–/–and control mice were fed ad libitum a high-fat diet (HFD, Harlan TD.88137) for 4 weeks. At the end of the treatment, FITC-Dextran was administered to mice by oral gavage. The serum concentration of FITC-dextran was measured. The serum lipids and liver function enzymes were measured using the Alfa Wassermann Vet ACE Axcel® System. Small intestine and liver tissues were processed for H&E staining and isolation of total RNA. Hepatic lipid was stained by Oil Red O. RNAseq transcriptome analysis was used to profile hepatic gene expression. The mRNA levels of the key genes were confirmed by qRT-PCR. Results Compared to control mice, the serum levels of FITC-Dextran were significantly higher in IE-HuR–/– mice fed an HFD. Consistently, the H&E staining of small intestine tissues revealed that the intestinal barrier was disrupted in IE-HuR–/– mice fed an HFD. Besides, the serum levels of ALP, ALT and AST significantly increased in HFD-fed IE-HuR–/– mice. The H&E and Oil Red O staining of liver tissues showed a significant increase in hepatic lipid accumulation in IE-HuR–/– mice. Bioinformatics analysis of RNAseq data showed that intestinal-specific deficiency of HuR significantly affected hepatic metabolic pathways, activated inflammatory and ER stress response. The qRT-PCR further confirmed that in IE-HuR–/– mice, the key genes involved in bile acid metabolisms (Cyp7a1, Cyp27a1, Cyp7b, and Cyp8b1) were significantly reduced, but the expression of genes involved in inflammation (Mcp-1, Il1α, Cd63, and Cxcl1) and endoplasmic reticulum stress (Chop, Atf4, Xbp-1s, and Grp78) were increased. Furthermore, the key genes involved in sphingosine lipid pathways, such as Smpd3 and Spt1c1, were significantly increased while the expression of Sphk2 was decreased. Conclusions Intestinal HuR deficiency exacerbates HFD-induced fatty liver disease via inducing intestinal barrier dysfunction, activating ER stress, and inflammatory response in the liver.