The food contaminant deoxynivalenol provokes metabolic impairments resulting in non-alcoholic fatty liver (NAFL) in mice

Rym Barbouche,Kevin Poirot,Anne Abysique,Coraline Airault,Jean-Denis Troadec,Stéphanie Gaigé,Michel Dallaporta

doi:10.1038/s41598-020-68712-w

Abstract

The ribotoxin deoxynivalenol (DON) is a trichothecene found on cereals responsible for mycotoxicosis in both humans and farm animals. DON toxicity is characterized by reduced food intake, diminished nutritional efficiency and immunologic effects. The present study was designed to further characterize the alterations in energy metabolism induced by DON intoxication. We demonstrated that acute DON intoxication triggered liver steatosis associated with an altered expression of genes related to lipids oxidation, lipogenesis and lipolysis. This steatosis was concomitant to anorexia, hypoglycemia and a paradoxical transient insulin release. DON treatment resulted also in stimulation of central autonomic network regulating sympathetic outflow and adrenaline and glucocorticoids secretion. Furthermore, an increased expression of genes linked to inflammation and reticulum endoplasmic stress was observed in the liver of DON-treated mice. Finally, we propose that lipids mobilization from adipose tissues (AT) induced by DON intoxication drives hepatic steatosis since (1) genes encoding lipolytic enzymes were up-regulated in AT and (2) plasma concentration of triglycerides (TGs) and non-esterified fatty acids were increased during DON intoxication. Altogether, these data demonstrate that DON induced hormonal and metabolic dysregulations associated with a spectrum of hepatic abnormalities, evocative of a non-alcoholic fatty liver disease.

Highlights

Abbreviations Acaca Acetyl-CoA carboxylase Alpha Acadm Acyl-CoA Dehydrogenase Medium Chain ADRP Adipose Differentiation-Related Protein AP Area postrema ATF6 Activating transcription factor 6 ATGL Adipose triglyceride lipase CACT Carnitine/Acylcarnitine Translocase (SLC25A20) CHOP C/EBP homologous protein Cpt-1 Carnitine Palmitoyltransferase 1 Cpt-2 Carnitine Palmitoyltransferase 2 DMNX Dorsal motor nucleus of the vagus Fasn Fatty acid synthase GAT Gonadic adipose tissue Hmgcr 3-Hydroxy-3-Methylglutaryl-CoA Reductase HSL Hormone-sensitive lipase IL-1β Interleukine-1β
It is largely admitted that a significant percentage of the human population is chronically exposed to DON doses which can exceed the provisional maximum tolerable daily dose in infants and children[3,4,5,6,7]
non-esterified fatty acids (NEFAs) released from adipose tissues through lipolysis are oxidized in hepatic mitochondria through fatty acid β-oxidation to provide energy to hepatocytes and ketone bodies which are exported into the circulation

Summary

Introduction

Abbreviations Acaca Acetyl-CoA carboxylase Alpha Acadm Acyl-CoA Dehydrogenase Medium Chain ADRP Adipose Differentiation-Related Protein AP Area postrema ATF6 Activating transcription factor 6 ATGL Adipose triglyceride lipase CACT Carnitine/Acylcarnitine Translocase (SLC25A20) CHOP C/EBP homologous protein Cpt-1 Carnitine Palmitoyltransferase 1 Cpt-2 Carnitine Palmitoyltransferase 2 DMNX Dorsal motor nucleus of the vagus Fasn Fatty acid synthase GAT Gonadic adipose tissue Hmgcr 3-Hydroxy-3-Methylglutaryl-CoA Reductase HSL Hormone-sensitive lipase IL-1β Interleukine-1β. DON treatment induced an up-regulation of ATGL and HSL mRNA expression as early as 3 h (Fig. 8A, B).

Results

Conclusion