Related Experiment Video
Updated: Aug 25, 2025
Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
Published on: January 31, 2025
Remodeling of Liver and Plasma Lipidomes in Mice Lacking Cyclophilin D
Balazs Koszegi1, Gabor Balogh2, Zoltan Berente1,3
1Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, 7624 Pecs, Hungary.
Abstract:
In recent years, several studies aimed to investigate the metabolic effects of non-functioning or absent cyclophilin D (CypD), a crucial regulatory component of mitochondrial permeability transition pores. It has been reported that the lack of CypD affects glucose and lipid metabolism. However, the findings are controversial regarding the metabolic pathways involved, and most reports describe the effect of a high-fat diet on metabolism. We performed a lipidomic analysis of plasma and liver samples of CypD-/- and wild-type (WT) mice to reveal the lipid-specific alterations resulting from the absence of CypD. In the CypD-/- mice compared to the WT animals, we found a significant change in 52% and 47% of the measured 225 and 201 lipid species in liver and plasma samples, respectively. The higher total lipid content detected in these tissues was not accompanied by abdominal fat accumulation assessed by nuclear magnetic resonance imaging. We also documented characteristic changes in the lipid composition of the liver and plasma as a result of CypD ablation with the relative increase in polyunsaturated membrane lipid species. In addition, we did not observe remarkable differences in the lipid distribution of hepatocytes using histochemistry, but we found characteristic changes in the hepatocyte ultrastructure in CypD-/- animals using electron microscopy. Our results highlight the possible long-term effects of CypD inhibition as a novel therapeutic consideration for various diseases.
Insights
Absence of cyclophilin D (CypD) significantly alters lipid metabolism in mice, impacting liver and plasma lipid species without causing fat accumulation. These findings suggest CypD inhibition as a potential therapeutic strategy.
Area of Science:
- Mitochondrial biology
- Metabolic research
- Lipidomics
Background:
- Cyclophilin D (CypD) regulates mitochondrial permeability transition pores and influences metabolism.
- Previous studies on CypD's metabolic effects show controversial findings, particularly concerning high-fat diet impacts.
- Understanding CypD's role in lipid metabolism is crucial for potential therapeutic applications.
Purpose of the Study:
- To elucidate the specific lipid alterations in plasma and liver due to the absence of CypD.
- To investigate the impact of CypD deficiency on overall lipid content and distribution.
- To explore the cellular and subcellular changes associated with CypD ablation.
Main Methods:
- Lipidomic analysis of plasma and liver samples from CypD knockout (CypD-/-) and wild-type (WT) mice.
- Nuclear magnetic resonance (NMR) imaging to assess abdominal fat accumulation.
- Histochemistry and electron microscopy to examine hepatocyte lipid distribution and ultrastructure.
Main Results:
- Significant changes (52% in liver, 47% in plasma) in measured lipid species were observed in CypD-/- mice compared to WT.
- Increased total lipid content in liver and plasma was not associated with increased abdominal fat.
- Characteristic alterations in lipid composition, including increased polyunsaturated membrane lipids, were identified in CypD-/- mice.
Conclusions:
- CypD deficiency profoundly impacts systemic lipid profiles, particularly in the liver and plasma.
- Hepatocyte ultrastructure is altered in CypD-/- mice, suggesting a role in cellular integrity.
- Long-term CypD inhibition may represent a novel therapeutic avenue for metabolic and other diseases.
