MPEP Attenuates Intrahepatic Fat Accumulation in Obese Mice
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Updated: Aug 3, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Andrea Ferrigno1,2, Marta Cagna1, Oriana Bosco1
1Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
Abstract:
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 ob/ob 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.
Insights
Blocking metabotropic glutamate receptor type 5 (mGluR5) with MPEP reduced fat accumulation and oxidative stress in a mouse model of steatosis. This study provides the first in vivo evidence of MPEP
Area of Science:
- Hepatology
- Metabolic Disorders
- Neuropharmacology
Background:
- Metabotropic glutamate receptor type 5 (mGluR5) blockade showed potential in reducing fat accumulation in cell models.
- Steatosis, characterized by fat buildup in the liver, is a growing health concern with limited treatment options.
Purpose of the Study:
- To investigate the in vivo efficacy of mGluR5 blockade using MPEP in a high-fat diet-induced mouse model of steatosis.
- To elucidate the molecular mechanisms underlying MPEP's effects on liver fat accumulation, oxidative stress, and inflammation.
Main Methods:
- Male ob/ob mice on a high-fat diet were treated with MPEP or vehicle for 7 weeks.
- Liver tissues were analyzed for lipid content, collagen deposition, oxidative stress markers (ROS, lipid peroxidation), and key protein/gene expression (PPARα, SREBP-1, mTOR, NF-κB, Acox1, Acc1, Il-6, Il1β, Tnf-α, Nrf2).
Main Results:
- MPEP treatment significantly reduced hepatic steatosis and hepatocyte ballooning compared to vehicle.
- MPEP administration led to increased nuclear PPARα and decreased nuclear SREBP-1 levels, alongside changes in their target genes.
- Oxidative stress, NF-κB activation, and inflammatory markers were significantly reduced in the MPEP group.
Conclusions:
- MPEP, a selective mGluR5 negative allosteric modulator, effectively reduces fat accumulation and oxidative stress in a murine model of steatosis.
- The findings suggest a therapeutic potential for mGluR5 blockade in managing non-alcoholic fatty liver disease (NAFLD).
- Further research is warranted to fully understand the underlying mechanisms and long-term effects of MPEP in steatosis.
