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

doi:10.1016/j.isci.2022.103766

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

iScience. 2022 Jan 12;25(2):103766. doi: 10.1016/j.isci.2022.103766. eCollection 2022 Feb 18.

Authors

Keerthana Balamurugan^{1

2}, Raghavender Medishetti¹, Jyothi Kotha³, Parameshwar Behera¹, Kanika Chandra^{1

2}, Vijay Aditya Mavuduru³, Manjunath B Joshi², Ramesh Samineni¹, Madhumohan R Katika⁴, Writoban Basu Ball³, Manjunatha Thondamal³, Anil Challa⁵, Kiranam Chatti¹, Kishore V L Parsa¹

Affiliations

¹ Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India.
² Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India.
³ Department of Biological Sciences, School of Engineering and Applied Sciences, SRM University AP, Guntur, Andhra Pradesh, India.
⁴ Stem Cell and Regenerative Medicine Department, Nizam's Institute of Medical Sciences, Hyderabad, India.
⁵ University of Alabama at Birmingham, Public University in Birmingham, Birmingham, AL, USA.

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.

Keywords: Biological sciences; Lipid; Molecular biology; Molecular physiology.