Ren Zhang, PhD

Ren Zhang, PhD
Associate Professor of Molecular Medicine and Genetics
Scott Hall, Rm 3319
540 E. Canfield St
Detroit, MI 48201
313-577-0027
rzhang@med.wayne.edu

Education

UT MD Anderson Cancer Center, PhD, 2005

Research Focus

Metabolism in health and disease. Metabolic syndrome is becoming a public health burden. The Ren Zhang lab identified two novel metabolism regulators: 1) lipasin and 2) MNADK (later known as ANGPTL8 and NADK2, respectively), both being encoded by previously uncharacterized genes. The lab studies the functions and mechanisms of ANGPTL8 and NADK2 in mediating lipid and glucose metabolism.

 

1) ANGPTL8 regulates triglyceride partitioning between fat and oxidative tissues. The human body stores energy during feasting while using the energy that has been stored during famine, a mechanism that helped human ancestors survive during evolution. As a fundamental physiological process, triglyceride (TG, the main energy source) is stored in white adipose tissue (WAT) after food intake while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning.

The Zhang lab initially identified lipasin (later known as ANGPTL8) as a novel TG metabolism regulator, and then proposed the ANGPTL3-4-8 model, which explains the mechanism for TG partitioning during the fed-fast cycle (Fig. 1). Research on ANGPTL3, 4, and 8 can hopefully provide more insights into human health, disease, and therapeutics.

 

Fig. 1. The ANGPTL3-4-8 model. ANGPTL3, 4 and 8 regulate TG partitioning during the fed-fast cycle. A) Food intake strongly induces A8 expression in the liver and WAT. Liver A3-8 complexes, in an endocrine manner, inhibit lipoprotein lipase (LPL) in oxidative tissues, while WAT A4-8 complexes protect LPL from being inhibited. Therefore, postprandial LPL activity is low in oxidative tissues but is high in WAT, directing TG to WAT for storage. B) Fasting induces WAT A4, which acts locally to inhibit LPL, while reduced liver A8 expression restores oxidative tissue LPL activity. Therefore, fasting LPL activity is low in WAT but high in oxidative tissues, enabling TG uptake into the latter for oxidation.

 
 
2) MNADK phosphorylates NAD+ to generate mitochondrial NADP+. Nicotinamide adenine dinucleotide (NAD), a coenzyme, is essential for metabolism. NAD phosphate (NADP) and its reduced form NADPH play crucial roles for fatty acid β-oxidation and for neutralizing reactive oxygen species (ROS). Mitochondria are an important source of ROS, but because NADP+ cannot pass through the mitochondrial membrane, the source of human mitochondrial NADP+ remained elusive for years. The Zhang lab discovered that the uncharacterized human gene C5ORF33 encodes the long-sought mitochondrion-localized NAD kinase, named MNADK (later known as NADK2). MNADK phosphorylates NAD+ to generate mitochondrial NADP+. Later studies showed that MNADK-deficient patients exhibit symptoms characteristic of mitochondrial disease, and that Mnadk knockout mice phenocopy the MNADK-deficient patients. MNADK is critical for generating mitochondrial NADP(H) and for maintaining its redox balance in mammalian cells (Fig. 2).  

Fig. 2. MNADK and NADK de novo generate NADP+ in mitochondria and cytosol, respectively.

Mentoring

Accepting new M.S. students in 2022/2023

Accepting new Ph.D students in 2022/2023

Recent Publications

 
        Comprehensive and authoritative, Essential Genes and Genomes: Methods and Protocols is an ideal guide for researchers attempting to strip genetics down to its fundamentals.  

Among the 10 most cited articles published by Open Biology in the past decade.

  • Fu Z, Abou-Samra AB, ZHANG R. A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase. Sci Rep. 2015; 5:18502.

  • ZHANG R. MNADK, a Long-Awaited Human Mitochondrion-Localized NAD Kinase. J Cell Physiol. 2015;230:1697-701.

  • Zhang C, ZHANG R. More effective glycaemic control by metformin in African Americans than in Whites in the prediabetic population. Diabetes Metab. 2015;41:173-5.

  • Zhang C, Luo H, Gao F, Zhang CT, ZHANG R. A reduction in both visceral and subcutaneous fats contributes to increased adiponectin by lifestyle intervention in the Diabetes Prevention Program. Acta Diabetol. 2015;52:625-8.

  • Zhang C, Gao F, Luo H, Zhang CT, ZHANG R. Differential response in levels of high-density lipoprotein cholesterol to one-year metformin treatment in prediabetic patients by race/ethnicity. Cardiovasc Diabetol. 2015;14:79.

  • Gao F, Luo H, Fu Z, Zhang CT, ZHANG R. Exome sequencing identifies novel ApoB loss-of-function mutations causing hypobetalipoproteinemia in type 1 diabetes. Acta Diabetol. 2015;52:531-7.

  • Gao F, Luo H, Zhang CT, ZHANG R. Gene essentiality analysis based on DEG 10, an updated database of essential genes. Methods Mol Biol. 2015;1279:219-33.

  • ZHANG R, Abou-Samra AB. A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy. Cardiovasc Diabetol. 2014;13:133.

  • Luo H, Lin Y, Gao F, Zhang CT, ZHANG R. DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements. Nucleic Acids Res. 2014;42:D574-80.

Highly Cited Paper”, selected by Web of Science (Thomson Reuters) as the citation being at top 1% of the academic field of Biology & Biochemistry.

  • Kim H, Mendez R, Zheng Z, Chang L, Cai J, ZHANG R, Zhang K. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor alpha to regulate metabolic hormone FGF21. Endocrinology. 2014;155:769-82.

  • Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, ZHANG R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci Rep. 2014;4:5013.

Highly Cited Paper”, selected by Web of Science (Thomson Reuters) as the citation being at top 1% of the academic field of Biology & Biochemistry.

Among the Most Cited BBRC Articles Since 2011” and “the Most Cited BBRC Articles Since 2012” selected by Elsevier.

  • ZHANG R, Lin Y. DEG 5.0, a database of essential genes in both prokaryotes and eukaryotes. Nucleic Acids Res. 2009, 37:D455-8.

  • ZHANG R, Maratos-Flier E, Flier JS. Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phosphodiesterase 4B. Endocrinology. 2009;150:3076-82.

  • ZHANG R, Dhillon H, Yin H, Yoshimura A, Lowell BB, Maratos-Flier E, Flier JS. Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology. 2008;149:5654-61.

  • ZHANG R, Murakami S, Coustry F, Wang Y, de Crombrugghe B. Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. PNAS. 2006;103:365-70.

The complete list of publications at NCBI My Bibliography and Google Scholar.