Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin

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Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin

Preeclampsia (PE)—a pregnancy complication marked by high blood pressure and organ damage—affects 5-8% of pregnancies worldwide and is a leading cause of maternal and fetal death. Despite its prevalence, its exact cause remains poorly understood, and treatment options are limited. Now, a 2019 study from researchers at Peking University Third Hospital sheds light on a potential link between a key cellular pathway, fatty acid metabolism, and how a common cholesterol-lowering drug might help.

The Problem: Fatty Acid Metabolism and Preeclampsia

Fatty acid oxidation (FAO)—the process where cells break down fatty acids for energy—is critical during pregnancy, when the body needs extra fuel for both mother and fetus. But in some PE cases, FAO goes haywire: fatty acids build up in the liver and placenta, and levels of free fatty acids (FFA)—harmful when too high—spike. One key enzyme for FAO is LCHAD (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase), which helps break down long-chain fatty acids. Previous research has shown LCHAD levels drop in the placentas of women with severe PE, linked to higher FFA levels and worse outcomes.

Enter mTOR (mammalian target of rapamycin): a protein kinase that acts as a “master regulator” of cell growth, metabolism, and survival. It’s activated by hormones, nutrients, and stress—and when overactive, it’s linked to diseases like cancer, diabetes, and now, possibly PE. Earlier studies found mTOR is overactive in the placentas of women with PE and gestational diabetes, but how this relates to FAO was unclear.

The Study: A Mouse Model of Preeclampsia

To explore the connection, the Peking University team created a PE-like mouse model using L-NAME (a drug that blocks nitric oxide, a molecule that helps blood vessels relax). L-NAME-treated mice develop high blood pressure, proteinuria (a sign of kidney damage), and FAO problems—mirroring human PE.

They divided 32 pregnant mice into four groups:

  1. L-NAME + saline: PE model, no treatment
  2. L-NAME + pravastatin: PE model, treated with 5mg/kg/day of pravastatin (a statin) via gavage from day 8–18 of pregnancy
  3. Control + saline: Normal pregnancy, no treatment
  4. Control + pravastatin: Normal pregnancy, treated with pravastatin

On day 18 (near term in mice), the researchers sacrificed the mice and collected liver and placenta tissues. They measured:

  • mTOR activation (via p-mTOR, the “active” form of mTOR)
  • LCHAD levels (the FAO enzyme)
  • Serum FFA levels (a marker of FAO dysfunction)
  • Activation of mTOR’s downstream targets (S6K1 and 4EBP1, which control protein synthesis and metabolism)

Key Findings: mTOR Overactivity and Pravastatin’s Effect

The results were striking:

  • mTOR was overactive in PE mice: In the L-NAME + saline group, the ratio of p-mTOR (active) to total mTOR was 30–40% higher in both liver and placenta compared to normal controls. This overactivity was linked to lower LCHAD levels (worse FAO) and higher FFA levels (more fatty acid buildup).
  • Pravastatin reduced mTOR activation: When PE model mice were treated with pravastatin, the p-mTOR/mTOR ratio fell by 13% in the liver and 18% in the placenta—closer to levels seen in normal pregnancy.
  • Correlations with FAO: In the untreated PE group, higher mTOR activation strongly correlated with lower LCHAD (liver: r=-0.745, placenta: r=-0.833; both P<0.05). In the pravastatin-treated PE group, lower mTOR activation correlated with higher LCHAD (liver: r=-0.733, P<0.05) and lower FFA (liver: r=0.841, P<0.05).

What Does This Mean for Preeclampsia?

These findings suggest mTOR overactivity drives FAO dysfunction in PE—and that pravastatin might help by inhibiting mTOR. Here’s why:
Pravastatin is a statin, a class of drugs that blocks HMG-CoA reductase (an enzyme needed for cholesterol synthesis). But statins have “pleiotropic” effects—benefits beyond lowering cholesterol. One key effect: reducing molecules like mevalonic acid and farnesyl pyrophosphate, which are needed to activate Rheb (a small G-protein that turns on mTOR). Without these molecules, Rheb can’t activate mTOR—effectively “turning down” the overactive pathway.

For PE, this is a game-changer. Pravastatin is already used safely in millions of people for high cholesterol, and previous studies from the same team showed it reduces PE-like symptoms in mice (lowering blood pressure, reducing proteinuria, and improving FAO). Now, this study links those benefits to mTOR inhibition.

Limitations and Future Directions

It’s important to note this is a mouse study—results don’t always translate to humans. The L-NAME model mimics the vascular problems of PE but not all its causes, and human PE is more complex. Further research is needed to confirm these findings in human tissues and test pravastatin in clinical trials for PE.

Why This Matters

PE remains a major global health challenge, with few targeted treatments. This study offers a promising new direction: by targeting mTOR, clinicians might one day use pravastatin to improve FAO and reduce PE’s severity. As the authors note, “The inhibition of mTOR signaling pathway might be involved in the regulation of FAO in mouse models treated with pravastatin”—a small step toward better care for women with PE.

Original Study: Huai J, Yang Z, Yi YH, Wang GJ. Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin. Chinese Medical Journal 2019;132:671–679. doi.org/10.1097/CM9.0000000000000129

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