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

Keerthana Balamurugan, Raghavender Medishetti, Jyothi Kotha, Parameshwar Behera, Kanika Chandra, Vijay Aditya Mavuduru, Manjunath B. Joshi, Ramesh Samineni, Madhumohan R. Katika, Writoban Basu Ball, Manjunatha Thondamal, Anil Challa, Kiranam Chatti, Kishore V.L. Parsa

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number103766
Pages (from-to)103766
JournaliScience
Volume25
Issue number2
DOIs
Publication statusPublished - 18-02-2022

All Science Journal Classification (ASJC) codes

  • General

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