Sodium salicylate rewires hepatic metabolic pathways in obesity and attenuates IL-1β secretion from adipose tissue: The implications for obesity-impaired reverse cholesterol transport.

Autor:	Kajani S; Diabetes Complications Research Centre, Ireland; UCD School of Medicine, Ireland; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland., Curley S; Diabetes Complications Research Centre, Ireland; UCD School of Medicine, Ireland; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland., O'Reilly ME; Diabetes Complications Research Centre, Ireland; UCD School of Medicine, Ireland; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland., Yin X; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland; School of Agriculture and Food Science, University College Dublin, Dublin 4, Ireland., Dillon ET; Mass Spectrometry Resource, Ireland., Guo W; Diabetes Complications Research Centre, Ireland; UCD School of Medicine, Ireland; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland., Nilaweera KN; Teagasc Food Research Centre, Ireland; VistaMilk Research Centre, Moorepark, Fermoy, Ireland., Brennan L; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland; School of Agriculture and Food Science, University College Dublin, Dublin 4, Ireland., Roche HM; Diabetes Complications Research Centre, Ireland; UCD Conway Institute, Ireland; Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports Science, Ireland; UCD Institute of Food and Health, Ireland., McGillicuddy FC; Diabetes Complications Research Centre, Ireland; UCD School of Medicine, Ireland; UCD Conway Institute, Ireland; UCD Institute of Food and Health, Ireland. Electronic address: fiona.mcgillicuddy@ucd.ie.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Feb; Vol. 56, pp. 101425. Date of Electronic Publication: 2021 Dec 24.
DOI:	10.1016/j.molmet.2021.101425
Abstrakt:	Introduction: High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, namely ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). In the current study, we hypothesized that the development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and that such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS). Materials and Methods: C57BL/6J mice, fed HFD ± NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing. The 3 H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analyzed using Ingenuity Pathway Analysis. Results: NaS delayed HFD-induced weight gain, abrogated priming of pro-IL-1β in SVFs, attenuated insulin resistance, and prevented steatohepatitis (ectopic fat accumulation in the liver). Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins. The latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection shown against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter, ABCG5/8, could not be rescued with NaS. Discussions and Conclusions: The cardiometabolic health benefits of NaS may be attributed to the reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the settings of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie the lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis. (Copyright © 2021. Published by Elsevier GmbH.)
Databáze:	MEDLINE
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