ApoE enhances mitochondrial metabolism via microRNA-142a/146a-regulated circuits that suppress hematopoiesis and inflammation in hyperlipidemia
Tuan Anh Phu,
Ngan K. Vu,
Martin Ng,
Alex S. Gao,
Joshua S. Stoolman,
Navdeep S. Chandel,
Robert L. Raffai
Affiliations
Tuan Anh Phu
Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Ngan K. Vu
Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Martin Ng
Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Alex S. Gao
Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Joshua S. Stoolman
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Navdeep S. Chandel
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Biochemistry & Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Robert L. Raffai
Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Surgery, Division of Endovascular and Vascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of tricarboxylic acid (TCA) cycle metabolites and nicotinamide adenine dinucleotide (NAD+) in macrophages. The study of mice with conditional ApoE expression supports the capacity of ApoE to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists, respectively, improves mitochondrial metabolism, which suppresses inflammation and hematopoiesis. Our findings unveil microRNA regulatory circuits, controlled by ApoE, that exert metabolic control over hematopoiesis and inflammation in hyperlipidemia.
