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
Affiliations
Keerthana Balamurugan
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India; Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
Raghavender Medishetti
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India
Jyothi Kotha
Department of Biological Sciences, School of Engineering and Applied Sciences, SRM University AP, Guntur, Andhra Pradesh, India
Parameshwar Behera
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India
Kanika Chandra
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India; Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
Vijay Aditya Mavuduru
Department of Biological Sciences, School of Engineering and Applied Sciences, SRM University AP, Guntur, Andhra Pradesh, India
Manjunath B. Joshi
Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
Ramesh Samineni
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India
Madhumohan R. Katika
Stem Cell and Regenerative Medicine Department, Nizam's Institute of Medical Sciences, Hyderabad, India
Writoban Basu Ball
Department of Biological Sciences, School of Engineering and Applied Sciences, SRM University AP, Guntur, Andhra Pradesh, India
Manjunatha Thondamal
Department of Biological Sciences, School of Engineering and Applied Sciences, SRM University AP, Guntur, Andhra Pradesh, India
Anil Challa
University of Alabama at Birmingham, Public University in Birmingham, Birmingham, AL, USA
Kiranam Chatti
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India; Corresponding author
Kishore V.L. Parsa
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India; Corresponding author
Summary: 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.
