PHLPP1 promotes neutral lipid accumulation through AMPK/ChREBP-dependent lipid uptake and fatty acid synthesis pathways

• Published in: iScience 2022-02, Vol.25 (2), p.103766-103766, Article 103766
• Main Authors: Balamurugan, Keerthana, Medishetti, Raghavender, Kotha, Jyothi, Behera, Parameshwar, Chandra, Kanika, Mavuduru, Vijay Aditya, Joshi, Manjunath B., Samineni, Ramesh, Katika, Madhumohan R., Ball, Writoban Basu, Thondamal, Manjunatha, Challa, Anil, Chatti, Kiranam, Parsa, Kishore V.L.
• Format: Article
• Language: English
• Subjects: Biological sciences; Lipid; Molecular biology; Molecular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.103766

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. [Display omitted] •PHLPP1 levels are elevated in OxLDL exposed macrophages and HFD-fed zebrafish larvae•Loss of PHLPP1 reduces neutral lipid build-up in macrophages, zebrafish, and C. elegans•PHLPP1 impairs pathways linked to lipid metabolism and inflammation•PHLPP1-dependent lipid build-up involves AMPK and ChREBP pathways Biological sciences; Lipid; Molecular physiology; Molecular biology