PEOPLE

Liming Pei, PhD

Assistant Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact InformationCTRB 6018
3501 Civic Center Blvd.
Philadelphia, PA 19104
Office: 267-425-2118
Fax: 267-426-0978

Email: lpei@pennmedicine.upenn.edu

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Cardiac Endocrinology; Mitochondrial Function and Metabolic Disease

The overall goal of the lab is to understand how different organs react to energy cues and communicate with each other to maintain whole-organism homeostasis in both physiological and pathological contexts. We welcome postdoctoral fellows and (rotating) graduate students to join us in our endeavors.

1. Cardiac endocrinology
A central question in physiology is how different organs communicate with each other to maintain whole-organism homeostasis. Research in the past 20 years revealed that non-glandular organs such as adipose tissue, liver and skeletal muscle can secrete hormones that regulate whole-body metabolism. In contrast, little is known regarding heart-derived hormones save for ANP and BNP, each discovered over 30 years ago. We recently discovered that Growth Differentiation Factor 15 (GDF15) is a new heart-derived hormone. Circulating GDF15 acts on the liver to inhibit growth hormone signaling and body growth. Plasma GDF15 is increased in children with concomitant heart disease and failure to thrive (FTT). Our results explain a well-established clinical observation that children with heart diseases often develop FTT. More importantly, these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Plasma GDF15 was recently shown to be elevated in patients with various heart diseases and is associated with increased morbidity and mortality. However, how GDF15 is increased in heart disease remains unclear. We tackled this clinically important question and identified the whole gene regulatory network that induces GDF15 transcription in heart disease, using massively parallel single-nucleus RNA-Seq (~20,000 nuclei). This study also revealed for the first time the organ composition, cell type and heterogeneity in normal postnatal, developing mouse heart, and the profound changes of transcriptional landscape of every cell type in the disease state. In addition, we have identified the key enzymes that process GDF15 pro-hormone into its mature form. Together, these studies helped pioneer a new field of cardiac endocrinology.

Hu P, Liu J, Zhao J, Wilkins BJ, Lupino K, Wu H, Pei L. (2018). Single-nucleus transcriptomic survey of cell diversity and functional remodeling in the postnatal developing hearts. Genes & Development.
Li J, Liu J, Lupino K, Liu X, Zhang L, Pei L. (2018). GDF15 maturation requires proteolytic cleavage by PCSK3, 5 and 6. Molecular and Cellular Biology.
Wang T, Liu J, McDonald C, Lupino K, Zhai X, Wilkins BJ, Hakonarson H, Pei L. (2017). GDF15 is a heart-derived hormone that regulates body growth. EMBO Mol Med

Ongoing/rotation projects:
a) Single cell analysis of postnatal mouse hearts to understand how heart disease affects cardiac functions at single cell level;
b) Single cell analysis to mechanistically understand specific disease conditions that induce GDF15 transcription;
c) Investigating how heart disease impacts GDF15 maturation through regulating the activity of GDF15 processing enzymes PCSK3, 5 and 6.
d) Identify the liver GDF15 receptor and elucidate its signaling pathway in the liver.

2. Cell type-specific regulation of cellular metabolism
Metabolic dysfunction directly causes or significantly contributes to many human diseases including heart disease, obesity, diabetes, cancer and aging. Most cells have limited capacity to store energy; therefore cellular energy supply and demand must be coordinated. In addition, different cell types exhibit preference for specific metabolic pathways (fatty acid oxidation/FAO, glycolysis or oxidative phosphorylation/OxPhos). For instance, neurons rely on glycolysis and ensuing OxPhos but not FAO, while cardiomyocytes use OxPhos and FAO to generate most energy for cardiac contraction. However, it is little understood how specific metabolic pathways are coordinately regulated to support cell type-specific function. Work from my lab using cell type-specific KO mice and genomic approaches (ChIP-Seq and RNA-Seq) filled this knowledge gap by identifying the transcription factor estrogen-related receptor gamma (ERRγ) as a key transcriptional coordinator of cellular energy supply and demand. Mechanistically we showed that ERRγ directly regulates hundreds of OxPhos genes, and cooperates with distinct transcription factors to regulate cell type-specific metabolic (FAO) and functional genes. Accordingly, ERRγ is essential for normal cardiac contraction and conduction1, neuronal function and learning/memory, and renal reabsorption. Together, these studies revealed how cellular energy production and consumption are elegantly coordinated in a cell type-specific manner.

Zhao J, Lupino K, Wilkins BJ, Qiu C, Liu J, Omura Y, Allred AL, McDonald C, Susztak K, Barish GD, Pei L. (2018). Genomic integration of ERRgamma-HNF1beta regulates renal bioenergetics and prevents chronic kidney disease. PNAS.
Pei L*, Mu Y, Leblanc M, Alaynick W, Barish GD, Pankratz M, Tseng TW, Kaufman S, Liddle C, Yu RT, Downes M, Pfaff SL, Auwerx J, Gage FH, Evans RM. (2015). Dependence of Hippocampal Function on ERRgamma-Regulated Mitochondrial Metabolism. Cell Metabolism (*cocorresponding author)
Wang T, McDonald C, Petrenko NB, Leblanc M, Giguere V, Evans RM, Patel VV, Pei L. (2015). Estrogen-related receptor alpha (ERRalpha) and ERRgamma are essential coordinators of cardiac metabolism and function. Molecular and Cellular Biology

Ongoing/rotation projects:
a) Modulating ERRγ activity to prevent/ameliorate kidney disease;
b) Modulating ERRγ activity to prevent/ameliorate mitochondrial disease using human iPS cell and animal models.

Itmat Expertise

Metabolic regulation, mitochondrial function and human disease

Graduate Groups

Cell and Molecular Biology

Education

B.S. University of Science and Technology of China, 2000
Ph.D. UCLA, 2006

Specialty Certification

Postgraduate Training

Postdoctoral Fellowship, Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, 2006-2013

Awards and Honors

Guo Moruo Scholarship, University of Science and Technology of China, 2000
George J. Popjak Scholar, UCLA School of Medicine, 2005
NIDDK Scholarship, Keystone Symposia, 2005
Sarkaria Award, UCLA School of Medicine, 2006
Parker B. Francis Fellowship, 2009

Memberships and Professional Organizations

American Heart Association, 2006 - Present
American Society for Microbiology, 2014 - Present
American Diabetes Association, 2014 - Present
Society of Chinese Bioscientists in America, 2015 - Present

Web Links


Selected Publications

Single-nucleus transcriptomic survey of cell diversity and functional remodeling in the postnatal developing hearts

Hu P, Liu J, Zhao J, Wilkins BJ, Lupino K, Wu H, Pei L, Genes & Development, 2018

Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease

Zhao J, Lupino K, Wilkins BJ, Qiu C, Liu J, Omura Y, Allred AL, McDonald C, Susztak K, Barish GD, Pei L, PNAS, 2018, PMID:29735694

Read article

GDF15 maturation requires proteolytic cleavage by PCSK3, 5 and 6

Li J, Liu J, Lupino K, Liu X, Zhang L, Pei L, Molecular and Cellular Biology, 2018, PMID:30104250

Read article

Mitochondrial Etiology of Neuropsychiatric Disorders

Pei L, Wallace DC, Biological Psychiatry, 2017, PMID:29290371

Read article

GDF15 is a heart-derived hormone that regulates body growth

Wang T, Liu J, McDonald, C, Lupino K, Zhai X, Wilkins BJ, Hakonarson H, Pei L, EMBO Molecular Medicine 9(): 1150-1164, 2017, PMID:28572090

Read article

ERRalpha and ERRgamma are essential coordinators of cardiac metabolism and function

Wang, T., McDonald, C., Petrenko, N.B., Leblanc, M., Giguere, V., Evans, R.M., Patel, V.V., and Pei, L., Mol Cell Biol. 35(7): 1281-1298, 2015, PMID:25624346

Read article

Dependence of hippocampal function on ERRγ regulated mitochondrial metabolism

Pei, L., Mu, Y., Leblanc, M., Alaynick, W., Barish, G.D., Pankratz, M., Tseng, T.W., Kaufman, S., Liddle, C., Yu, R.T., Downes, M., Pfaff, S.L., Auwerx, J., Gage, F.H., Evans, R.M., Cell Metab 21(4): 628-636, 2015, PMID:25863252

Read article

Thyroid hormone receptor repression is linked to type I pneumocyte associated respiratory distress syndrome.

Pei, L., Leblanc, M., Barish, G., Atkins, A., Nofsinger, R., Whyte, J., Gold, D., He, M., Kawamura, K., Li, H-R., Downes, M., Yu, R., Powell, H.C., Lingrel, J.B., Evans, R.M., Nat Med 17(11): 1466-1472, 2011, PMID:22001906

Read article

Retrofitting fat metabolism

Pei, L., and Evans, R.M, Cell Metab 9(6): 483-484, 2009, PMID:19490901

Read article

NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism

Pei, L., Waki, H., Vaitheesvaran, B., Wilpitz, D. C., Kurland, I. J., and Tontonoz, P, Nat Med 12(9): 1048-1055, 2006, PMID:16906154

Read article

Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli

Pei, L., Castrillo, A., Chen, M., Hoffmann, A., Tontonoz, P., J Biol Chem 280(32): 29256-29262, 2005, PMID:15964844

Read article

Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77

Pei, L., Castrillo, A., and Tontonoz, P, Mol Endocrinol 20(4): 786-794, 2006, PMID:16339277

Read article

Fat's loss is bone's gain

Pei, L., Tontonoz, P., J Clin Invest 113(6): 805-6, 2004