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

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 e...

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Autores principales:	Martina Hüttl, Irena Markova, Denisa Miklankova, Iveta Zapletalova, Martin Poruba, Martin Haluzik, Ivana Vaněčkova, Hana Malinska
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	SGLT-2 inhibitors empagliflozin fatty liver lipid metabolism cytochrome P450 fetuin-A Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/5232f2e319d64d328a7424197deea0a9
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spelling	oai:doaj.org-article:5232f2e319d64d328a7424197deea0a92021-11-11T16:58:23ZIn a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia10.3390/ijms2221115131422-00671661-6596https://doaj.org/article/5232f2e319d64d328a7424197deea0a92021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11513https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Recent 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 (<i>Scd-1</i>, <i>Fas</i>) and transcription factors (<i>Srebp1</i>, <i>Pparγ</i>). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly <i>Cyp2e1</i> and <i>Cyp4a</i>, together with increased <i>Nrf2,</i> 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.Martina HüttlIrena MarkovaDenisa MiklankovaIveta ZapletalovaMartin PorubaMartin HaluzikIvana VaněčkovaHana MalinskaMDPI AGarticleSGLT-2 inhibitorsempagliflozinfatty liverlipid metabolismcytochrome P450fetuin-ABiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11513, p 11513 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SGLT-2 inhibitors empagliflozin fatty liver lipid metabolism cytochrome P450 fetuin-A Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	SGLT-2 inhibitors empagliflozin fatty liver lipid metabolism cytochrome P450 fetuin-A Biology (General) QH301-705.5 Chemistry QD1-999 Martina Hüttl Irena Markova Denisa Miklankova Iveta Zapletalova Martin Poruba Martin Haluzik Ivana Vaněčkova Hana Malinska In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
description	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 (<i>Scd-1</i>, <i>Fas</i>) and transcription factors (<i>Srebp1</i>, <i>Pparγ</i>). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly <i>Cyp2e1</i> and <i>Cyp4a</i>, together with increased <i>Nrf2,</i> 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.
format	article
author	Martina Hüttl Irena Markova Denisa Miklankova Iveta Zapletalova Martin Poruba Martin Haluzik Ivana Vaněčkova Hana Malinska
author_facet	Martina Hüttl Irena Markova Denisa Miklankova Iveta Zapletalova Martin Poruba Martin Haluzik Ivana Vaněčkova Hana Malinska
author_sort	Martina Hüttl
title	In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
title_short	In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
title_full	In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
title_fullStr	In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
title_full_unstemmed	In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia
title_sort	in a prediabetic model, empagliflozin improves hepatic lipid metabolism independently of obesity and before onset of hyperglycemia
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5232f2e319d64d328a7424197deea0a9
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In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia

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