In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia.

Martina Hüttl,Hana Malinska,Irena Markova,Martin Haluzik,Ivana Vaněčkova,Martin Poruba,Denisa Miklankova,Iveta Zapletalova

doi:10.3390/ijms222111513

Abstract

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, obesity, and various prediabetic states and is characterized by increased hepatic lipid accumulation (>5%)
There were no differences in initial body weight, glucose or serum triacylglycerols (TAG) between the control Wistar and Wistar + empa groups or between the prediabetic hereditary hypertriglyceridemic (HHTg) and HHTg + empa groups
Our results show that empagliflozin treatment in prediabetic rats can mitigate hepatic steatosis by reducing hepatic triacylglycerols as well as lipotoxic intermediates

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, obesity, and various prediabetic states and is characterized by increased hepatic lipid accumulation (>5%). Considered an independent risk factor for cardiovascular events [1,2], NAFLD markedly increases the risk of developing type 2 diabetes mellitus (T2DM) [3]. Along with impaired lipid metabolism and ectopic lipid deposition, dyslipidemia is one of the most common disorders linked to prediabetic conditions and is often preceded by the onset of hyperglycemia. Approximately 50% of obese individuals and up to 70% of diabetic patients exhibit characteristic features of fatty liver, NAFLD can occur in non-obese individuals. The prevalence of non-obese NAFLD ranges widely from 3 to 30% [4]. Despite the high prevalence of NAFLD, an effective therapy has yet to be developed

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