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Farnesoid X receptor activation induces the degradation of hepatotoxic 1-deoxysphingolipids in non-alcoholic fatty liver disease


Gai, Zhibo; Gui, Ting; Alecu, Irina; Lone, Museer A; Hornemann, Thorsten; Chen, Qingfa; Visentin, Michele; Hiller, Christian; Hausler, Stephanie; Kullak-Ublick, Gerd A (2019). Farnesoid X receptor activation induces the degradation of hepatotoxic 1-deoxysphingolipids in non-alcoholic fatty liver disease. Liver International:Epub ahead of print.

Abstract

BACKGROUND & AIMS
Patients with non-alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1-deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1-deoxysphingolipid de novo synthesis and degradation.
METHODS
Mice were fed with a high-fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography-mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1-deoxysphinganine-treated mouse model.
RESULTS
1-deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1-deoxysphingolipid levels, both in a HFD-induced mouse model of obesity and in 1-deoxysphinganine-treated mice. In vitro, FXR activation lowered intracellular 1-deoxysphingolipid levels by inducing Cyp4f-mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA-induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA-induced cytotoxicity. Treatment with the Cyp4f pan-inhibitor HET0016 or FXR knock-down fully abolished the protective effect of OCA, indicating that OCA-mediated 1-deoxysphingolipid degradation is FXR and Cyp4f dependent.
CONCLUSIONS
Our study identifies FXR-Cyp4f as a novel regulatory pathway for 1-deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.

Abstract

BACKGROUND & AIMS
Patients with non-alcoholic fatty liver disease (NAFLD) exhibit higher levels of plasma 1-deoxysphingolipids than healthy individuals. The aim of this study was to investigate the role of farnesoid X receptor (FXR) in 1-deoxysphingolipid de novo synthesis and degradation.
METHODS
Mice were fed with a high-fat diet (HFD) to induce obesity and NAFLD, and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Sphingolipid patterns from NAFLD patients and mouse models were assessed by liquid chromatography-mass spectrometry. The molecular mechanism underlying the effect of FXR activation on sphingolipid metabolism was studied in Huh7 cells and primary cultured hepatocytes, as well as in a 1-deoxysphinganine-treated mouse model.
RESULTS
1-deoxysphingolipids were increased in both NAFLD patients and mouse models. FXR activation by OCA protected the liver against oxidative stress, apoptosis, and reduced 1-deoxysphingolipid levels, both in a HFD-induced mouse model of obesity and in 1-deoxysphinganine-treated mice. In vitro, FXR activation lowered intracellular 1-deoxysphingolipid levels by inducing Cyp4f-mediated degradation, but not by inhibiting de novo synthesis, thereby protecting hepatocytes against doxSA-induced cytotoxicity, mitochondrial damage, and apoptosis. Overexpression of Cyp4f13 in cells was sufficient to ameliorate doxSA-induced cytotoxicity. Treatment with the Cyp4f pan-inhibitor HET0016 or FXR knock-down fully abolished the protective effect of OCA, indicating that OCA-mediated 1-deoxysphingolipid degradation is FXR and Cyp4f dependent.
CONCLUSIONS
Our study identifies FXR-Cyp4f as a novel regulatory pathway for 1-deoxysphingolipid metabolism. FXR activation represents a promising therapeutic strategy for patients with metabolic syndrome and NAFLD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Language:English
Date:28 December 2019
Deposited On:07 Feb 2020 10:29
Last Modified:12 Feb 2020 13:27
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1478-3223
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/liv.14340
PubMed ID:31883408

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