Copper-catalyzed dicarbonyl stress in NAFLD mice: protective effects of Oleuropein treatment on liver damage

Silvano Junior Santini,Anna Alisi,Giovanni Tarantino,Antonella Iezzi,Clara Balsano

doi:10.1186/s12986-022-00641-z

Abstract

BackgroundNonalcoholic fatty liver disease (NAFLD) or more appropriately, metabolic associated fatty liver disease (MAFLD), is the hepatic manifestation of metabolic syndrome. An imbalance of copper homeostasis has been described in the progression of NAFLD/MAFLD toward NASH/MASH. We were interested in understanding whether the chelating activity of Oleuropein (Ole) was able to improve the copper accumulation and the related pro-oxidant and glycative damage in the liver of mice fed HFD.MethodsTwelve C57BL/6J mice fed normal diet (ND) or high-fat diet (HFD) for 16 weeks and then thirty two female and male mice fed ND or HFD for 8 weeks adding Ole for the following 8 weeks were studied.ResultsAltered expression of copper-trafficking genes and proteins (CTR1, CTR2, ATP7B, COX17, CCS, and ATOX1) induced imbalance of copper homeostasis combined with an increase in dicarbonyl stress in the liver of HFD fed mice. Interestingly enough, glyoxalase system was improved by Ole administration and the Ole related protective effects differ in the two sexes of mice.ConclusionsOur study highlights the role of the dicarbonyl stress in the pathogenesis of NAFLD and suggests Ole as a natural copper chelator to prevent the liver damage induced by methyglyoxal pathway derangement.

Highlights

Nonalcoholic fatty liver disease (NAFLD) or more appropriately, metabolic associated fatty liver disease (MAFLD), is the hepatic manifestation of metabolic syndrome
To evaluate the role of copper in the pathogenesis of liver steatosis, we looked at the concentration of the biometal in the serum and liver tissues of a 16 weeks high-fat diet (HFD) fed mouse model
In HFD fed mice, the altered concentrations of copper were associated with the altered transcriptional expression of the copper-trafficking genes: CTR1 and ATP7B (Fig. 1c)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) or more appropriately, metabolic associated fatty liver disease (MAFLD), is the hepatic manifestation of metabolic syndrome. NAFLD (Nonalcoholic fatty liver disease), one of the major forms of chronic liver disease, is considered the hepatic manifestation of the metabolic syndrome (MetS), is currently called metabolic associated fatty liver disease (MAFLD) [1]. The hepatic metabolic homeostasis (glycolysis, gluconeogenesis, lipogenesis, and fatty acid oxidation) can be disrupted by various adverse conditions, one of them is the intratissue excess of copper, deeply implicated in the formation of reactive carbonyl compounds [5,6,7]. It has been highlighted enhanced glycolytic activity and higher. It is produced in l-threonine metabolism, catabolism of the ketone bodies acetoacetate and acetone and as a by-product of glycolysis [11,12,13]

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