Dataset Information

Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury.

ABSTRACT:

Background

Intestinal barrier dysfunction is crucial in alcohol-associated liver disease (ALD). The decreased beta-Klotho (KLB) expression caused by gene variation is associated with hyperpermeability in patients with irritable bowel syndrome. Here we investigated the roles of intestinal KLB in maintaining the intestinal epithelial barrier in ALD and the underlying mechanisms.

Methods

We constructed the intestine-specific overexpression KLB mice to investigate the role of KLB on alcohol-induced intestinal barrier dysfunction and liver injury in an ALD mouse model. To investigate the molecular mechanism in vitro, Caco2 cells were cultured and infected with the KLB overexpression lentivirus, or transfected with KLB/TRPV6 siRNA, or TRPV6/FXR1 overexpression plasmid, and treated with or without ethanol.

Findings

The upregulation of KLB in enterocytes effectively protected mice from alcohol-induced intestinal barrier hyperpermeability, thereby ameliorating hepatic steatosis and inflammation. KLB competitively suppressed FXR1 binding to the TRPV6 mRNA, increasing TRPV6 mRNA stability and protein abundance in intestinal epithelial cells. Furthermore, KLB formed a complex with TRPV6 and tight junction (TJ) proteins, protecting against alcohol-induced TJ proteins endocytosis and degradation as well as intestinal barrier impairment.

Interpretation

This work suggested that KLB attenuated alcohol-induced intestinal epithelial barrier dysfunction and liver injury through FXR1/TRPV6/TJ proteins pathway.

Funding

National Natural Science Foundation of China, Chongqing Natural Science Foundation, Talent Project of Chongqing and the Science and Technology Research Program of Chongqing Municipal Education Commission.

SUBMITTER: Hou Z

PROVIDER: S-EPMC9352463 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury.

Hou Zhengping Z Ding Qiuying Q Li Yuqi Y Zhao Zhibo Z Yan Fang F Li Yanping Y Wang Xingxing X Xu Jingyuan J Chen Weiting W Wu Guicheng G Ruan Xiongzhong X Zhao Lei L

EBioMedicine 20220728

<h4>Background</h4>Intestinal barrier dysfunction is crucial in alcohol-associated liver disease (ALD). The decreased beta-Klotho (KLB) expression caused by gene variation is associated with hyperpermeability in patients with irritable bowel syndrome. Here we investigated the roles of intestinal KLB in maintaining the intestinal epithelial barrier in ALD and the underlying mechanisms.<h4>Methods</h4>We constructed the intestine-specific overexpression KLB mice to investigate the role of KLB on a ...[more]

PMID: 35908416

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Project description:Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.

Dataset Information

Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury.

Background

Methods

Findings

Interpretation

Funding

Publications

Intestinal epithelial β Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury.

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