The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile.

Alana Aragón-Herrera,Esther Roselló-Lletí,Manuel Portolés,Isabel Moscoso,Francisca Lago,Laura Anido-Varela,José Ramón González-Juanatey,Manuel Campos-Toimil,Ricardo Lage,Estefanía Tarazón,Sandra Moraña-Fernández,Sandra Feijóo-Bandín,Oreste Gualillo,Luis Barral,Manuel Otero-Santiago,Tomás García-Caballero

doi:10.3389/fphar.2022.827033

Abstract

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.

Highlights

Type 2 diabetes mellitus (T2DM) is highly connected to metabolic liver disease, that is a chronic condition that implies hepatic fat accumulation associated to underpinning metabolic dysregulation (Lim et al, 2021) and low-grade inflammation (Furman et al, 2019; Watt et al, 2019; Lim et al, 2021)
The Zucker diabetic fatty (ZDF) rat is a model of T2DM well established, and it is used as a model for the study of metabolic fatty liver disease (Shiota and Printz, 2012; Kucera, 2014)
Hepatic glycerides can be raised in metabolic liver disease, increasing data show that the total quantity of TG accumulated in the hepatic cells is not the principal cause of lipotoxicity, and that are specific classes of lipids those that act as damaging agents (Svegliati-Baroni et al, 2019)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) is highly connected to metabolic liver disease, that is a chronic condition that implies hepatic fat accumulation associated to underpinning metabolic dysregulation (Lim et al, 2021) and low-grade inflammation (Furman et al, 2019; Watt et al, 2019; Lim et al, 2021). This complex and bidirectional association raises the possibility of common mechanisms of disease treatment (Vincent et al, 2020; Gastaldelli et al, 2021). Empagliflozin treatment has been shown to be able to reduce fat hepatic content in T2DM patients with fatty liver disease (Kuchay et al, 2018) and in animal models of diabetes-associated steatohepatitis (Jojima et al, 2016; Petito-da-Silva et al, 2019; Xu et al, 2019)

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