PUBLICATION
PHLPP1 promotes neutral lipid accumulation through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways
- Authors
- Balamurugan, K., Medishetti, R., Kotha, J., Behera, P., Chandra, K., Mavuduru, V.A., Joshi, M.B., Samineni, R., Katika, M.R., Ball, W.B., Thondamal, M., Challa, A., Chatti, K., Parsa, K.V.L.
- ID
- ZDB-PUB-220211-4
- Date
- 2022
- Source
- iScience 25: 103766 (Journal)
- Registered Authors
- Challa, Anil Kumar, Chatti, Kiranam
- Keywords
- Biological sciences, Lipid, Molecular biology, Molecular physiology
- MeSH Terms
- none
- PubMed
- 35141506 Full text @ iScience
Citation
Balamurugan, K., Medishetti, R., Kotha, J., Behera, P., Chandra, K., Mavuduru, V.A., Joshi, M.B., Samineni, R., Katika, M.R., Ball, W.B., Thondamal, M., Challa, A., Chatti, K., Parsa, K.V.L. (2022) PHLPP1 promotes neutral lipid accumulation through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways. iScience. 25:103766.
Abstract
Infiltration of arterial intima by foamy macrophages is a hallmark of early atherosclerotic lesions. Here, we investigated the potential role of Ser/Thr phosphatase PHLPP1 in foam cell development. PHLPP1 levels were elevated in OxLDL-exposed macrophages and high-fat diet (HFD)-fed zebrafish larvae. Using overexpression and knockdown approaches, we show that PHLPP1 promotes the accumulation of neutral lipids, and augments cellular total cholesterol and free fatty acid (FFA) levels. RNA-Seq analysis uncovered PHLPP1 role in lipid metabolism pathways. PHLPP1 interacted with and modestly increased ChREBP recruitment to Fasn promoter. PHLPP1-mediated lipid accumulation was attenuated by AMPK activation. Pharmacological inhibition or CRISPR/Cas9-mediated disruption of PHLPP1 resulted in lower lipid accumulation in the intersegmental vessels of HFD-fed zebrafish larvae along with a reduction in total cholesterol and triglyceride levels. Deficiency of phlp-2, C. elegans PHLPP1/2 ortholog, abolished lipid accumulation in high cholesterol-fed worms. We conclude that PHLPP1 exerts a significant effect on lipid buildup.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping