MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice
The blockade of metabotropic glutamate receptor type 5 (mGluR5) was previously found to reduce fat accumulation in HEPG2 cells. Here, we evaluated the effects of mGluR5 blockade in a mouse model of steatosis. Male <i>ob/ob</i> mice fed a high-fat diet were treated with MPEP or vehicle. A...
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6076 |
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| author | Andrea Ferrigno Marta Cagna Oriana Bosco Michelangelo Trucchi Clarissa Berardo Ferdinando Nicoletti Mariapia Vairetti Laura G. Di Pasqua |
| author_facet | Andrea Ferrigno Marta Cagna Oriana Bosco Michelangelo Trucchi Clarissa Berardo Ferdinando Nicoletti Mariapia Vairetti Laura G. Di Pasqua |
| author_sort | Andrea Ferrigno |
| collection | DOAJ |
| description | The blockade of metabotropic glutamate receptor type 5 (mGluR5) was previously found to reduce fat accumulation in HEPG2 cells. Here, we evaluated the effects of mGluR5 blockade in a mouse model of steatosis. Male <i>ob/ob</i> mice fed a high-fat diet were treated with MPEP or vehicle. After 7 weeks, liver biopsies were collected, and nuclei were isolated from fresh tissue. Lipid droplet area and collagen deposition were evaluated on tissue slices; total lipids, lipid peroxidation, and ROS were evaluated on tissue homogenates; PPARα, SREBP-1, mTOR, and NF-κB were assayed on isolated nuclei by Western Blot. Target genes of the above-mentioned factors were assayed by RT-PCR. Reduced steatosis and hepatocyte ballooning were observed in the MPEP group with respect to the vehicle group. Concomitantly, increased nuclear PPARα and reduced nuclear SREBP-1 levels were observed in the MPEP group. Similar trends were obtained in target genes of PPARα and SREBP-1, Acox1 and Acc1, respectively. MPEP administration also reduced oxidative stress and NF-κB activation, probably via NF-κB inhibition. Levels of common markers of inflammation (Il-6, Il1β and Tnf-α) and oxidative stress (Nrf2) were significantly reduced. mTOR, as well as collagen deposition, were unchanged. Concluding, MPEP, a selective mGluR5 negative allosteric modulator, reduces both fat accumulation and oxidative stress in a 7-week murine model of steatosis. Although underlying mechanisms need to be further investigated, this is the first in vivo study showing the beneficial effects of MPEP in a murine model of steatosis. |
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| spelling | doaj.art-b164945d279e4700b9743315ab9ba7b82023-11-17T16:46:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01247607610.3390/ijms24076076MPEP Attenuates Intrahepatic Fat Accumulation in Obese MiceAndrea Ferrigno0Marta Cagna1Oriana Bosco2Michelangelo Trucchi3Clarissa Berardo4Ferdinando Nicoletti5Mariapia Vairetti6Laura G. Di Pasqua7Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyUnit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyUnit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyUnit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyDepartment of Biomedical and Clinical Science, University of Milano, 20157 Milano, ItalyDepartment of Physiology and Pharmacology, Sapienza University, 00185 Rome, ItalyUnit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyUnit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, ItalyThe blockade of metabotropic glutamate receptor type 5 (mGluR5) was previously found to reduce fat accumulation in HEPG2 cells. Here, we evaluated the effects of mGluR5 blockade in a mouse model of steatosis. Male <i>ob/ob</i> mice fed a high-fat diet were treated with MPEP or vehicle. After 7 weeks, liver biopsies were collected, and nuclei were isolated from fresh tissue. Lipid droplet area and collagen deposition were evaluated on tissue slices; total lipids, lipid peroxidation, and ROS were evaluated on tissue homogenates; PPARα, SREBP-1, mTOR, and NF-κB were assayed on isolated nuclei by Western Blot. Target genes of the above-mentioned factors were assayed by RT-PCR. Reduced steatosis and hepatocyte ballooning were observed in the MPEP group with respect to the vehicle group. Concomitantly, increased nuclear PPARα and reduced nuclear SREBP-1 levels were observed in the MPEP group. Similar trends were obtained in target genes of PPARα and SREBP-1, Acox1 and Acc1, respectively. MPEP administration also reduced oxidative stress and NF-κB activation, probably via NF-κB inhibition. Levels of common markers of inflammation (Il-6, Il1β and Tnf-α) and oxidative stress (Nrf2) were significantly reduced. mTOR, as well as collagen deposition, were unchanged. Concluding, MPEP, a selective mGluR5 negative allosteric modulator, reduces both fat accumulation and oxidative stress in a 7-week murine model of steatosis. Although underlying mechanisms need to be further investigated, this is the first in vivo study showing the beneficial effects of MPEP in a murine model of steatosis.https://www.mdpi.com/1422-0067/24/7/6076MPEPNAFLDNASHliverhigh-fat diet<i>ob/ob</i> mice |
| spellingShingle | Andrea Ferrigno Marta Cagna Oriana Bosco Michelangelo Trucchi Clarissa Berardo Ferdinando Nicoletti Mariapia Vairetti Laura G. Di Pasqua MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice International Journal of Molecular Sciences MPEP NAFLD NASH liver high-fat diet <i>ob/ob</i> mice |
| title | MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice |
| title_full | MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice |
| title_fullStr | MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice |
| title_full_unstemmed | MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice |
| title_short | MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice |
| title_sort | mpep attenuates intrahepatic fat accumulation in obese mice |
| topic | MPEP NAFLD NASH liver high-fat diet <i>ob/ob</i> mice |
| url | https://www.mdpi.com/1422-0067/24/7/6076 |
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