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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MDPI AG
2021-10-01
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:01:34Z |
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| id | doaj.art-5232f2e319d64d328a7424197deea0a9 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:01:34Z |
| publishDate | 2021-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5232f2e319d64d328a7424197deea0a92023-11-22T20:53:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211151310.3390/ijms222111513In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of HyperglycemiaMartina Hüttl0Irena Markova1Denisa Miklankova2Iveta Zapletalova3Martin Poruba4Martin Haluzik5Ivana Vaněčkova6Hana Malinska7Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14321 Prague, Czech RepublicCentre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14321 Prague, Czech RepublicCentre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14321 Prague, Czech RepublicDepartment of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech RepublicDepartment of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech RepublicDiabetes Centre, Institute for Clinical and Experimental Medicine, 14321 Prague, Czech RepublicDepartment of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech RepublicCentre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14321 Prague, Czech RepublicRecent 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.https://www.mdpi.com/1422-0067/22/21/11513SGLT-2 inhibitorsempagliflozinfatty liverlipid metabolismcytochrome P450fetuin-A |
| spellingShingle | 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 International Journal of Molecular Sciences SGLT-2 inhibitors empagliflozin fatty liver lipid metabolism cytochrome P450 fetuin-A |
| title | 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_short | 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 |
| topic | SGLT-2 inhibitors empagliflozin fatty liver lipid metabolism cytochrome P450 fetuin-A |
| url | https://www.mdpi.com/1422-0067/22/21/11513 |
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