Ren Zhang, PhD

Ren Zhang, PhD
Associate Professor of Molecular Medicine and Genetics and of Internal Medicine
Scott Hall, Rm 3319
540 E. Canfield St
Detroit, MI 48201


The University of Texas MD Anderson Cancer Center, PhD, 2005

Research Focus

Patients with metabolic syndrome are at high risk for developing atherosclerotic cardiovascular diseases and diabetes, a major public health burden. The Zhang lab recently identified two novel lipid metabolism regulators, (1) lipasin and (2) MNADK, both being encoded by previously uncharacterized genes. The lab currently focuses on the characterizations of functional roles of lipasin and MNADK in mediating lipid metabolism and glucose homeostasis.


(1) Lipasin/Angplt8, a novel lipid metabolism regulator. In addition to LDL-cholesterol, elevated plasma triglycerides are increasingly recognized as an independent risk factor for cardiovascular diseases. The Zhang lab recently identified a novel triglyceride metabolism regulator, encoded by a previously uncharacterized gene, Gm6484, which was then named lipasin, also known as RIFL and ANGPTL8. Serum triglyceride levels are decreased or increased in ANGPTL8-deficient or -overexpressing mice, respectively. ANGPTL8 expression, specific to the liver and adipose tissues, is dramatically induced by food intake and reduced by fasting. In humans, plasma levels of lipasin—which is secreted by the liver—are elevated in both type 1 and type 2 diabetes, and its sequence variations are associated with lipid profiles by multiple genome-wide association studies. ANGPTL8, ANGPTL3, and ANGPTL4 are coordinated to regulate lipid metabolism by inhibiting the activity of lipoprotein lipase at different physiological conditions (feeding vs. fasting) and pathological conditions (normal vs. diabetes). (Fig. 1)


Fig. 1. The ANGPTL3-4-8 model. ANGPTL8, ANGPTL3 and ANGPTL4 regulate triglyceride (TG) trafficking by inhibiting lipoprotein lipase, in a tissue-specific manner, under different nutritional statuses. The level of ANGPTL3 is stable, regardless of nutritional status, but it requires activation by ANGPTL8. Fasting induces ANGPTL4, which inhibits LPL in WAT to direct circulating TG to cardiac and skeletal muscles for oxidation (a); conversely, feeding induces ANGPTL8, activating the ANGPTL8–ANGPTL3 pathway, which inhibits LPL in cardiac and skeletal muscles to direct circulating TG to WAT for storage (b).

(2) MNADK represents a novel pathway in generating mitochondrial NADP. Nicotinamide adenine dinucleotide phosphate (NADP) plays essential roles in lipid metabolism. NADP is required by mitochondria for fatty acid β-oxidation to generate energy, and for regenerating oxidative defense systems to neutralize reactive oxygen species. The NAD kinase (NADK) is the sole NADP biosynthetic enzyme, but human mitochondrial NAD kinase remained unidentified for many years. The Zhang lab recently discovered that the uncharacterized human gene C5ORF33 encodes the long-sought mitochondrion-localized NADK, referred to as MNADK, also later known as NADK2. MNADK is a mitochondrial NADK that is enriched and nutritionally-regulated in mouse liver, and a MNADK-deficient patient exhibits symptoms characteristic of mitochondrial disease. Mnadk knockout mice phenocopy the MNADK-deficient patient by having elevated plasma lysine and C10:2 carnitine. The identification of MNADK provides a key clue to the mechanisms for mitochondrial NADP(H) production and the maintenance of its redox balance in mammalian cells (Fig. 2).  

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


Accepting new M.S. students in 2022/2023

Accepting new Ph.D students in 2022/2023

Recent Publications

  • Ren Zhang (Editor), 2022, Essential Genes and Genomes. Springer (10.1007/978-1-0716-1720-5)

  • Zhang R, Zhang K, An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues. 2021, Progress in Lipid Research, 85, 101140.

  • Zhang R, The Potential of ANGPTL8 Antagonism to Simultaneously Reduce Triglyceride and Increase HDL-Cholesterol Plasma Levels. 2021, Front. Cardiovasc. Med., 8, 795370.

  • Hao L, Yan L, Tao L, Lai F, Zhang C, Gao F, and ZHANG R. DEG 15, an update of the Database of Essential Genes that includes built-in analysis tools. Nucleic Acids Research, 2021, 49:D677-D686.

  • Kim H, Williams D, Qiu Y, Song Z, Yang Z, Kimler V, Goldberg A, ZHANG R, Yang Z, Chen X, Wang L, Fang D, Lin JD, Zhang K. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH. FASEB J. 2019, 33:7896-7914.

  • Zhang K, Kim H, Fu Z, Qiu Y, Yang Z, Wang J, Zhang D, Tong X, Yin L, Li J, Wu J, Qi NR, Houten SM, ZHANG R. Deficiency of the mitochondrial NAD kinase causes stress-induced non-alcoholic steatohepatitis. Gastroenterology, 2018, 154: 224–237.

  • Chi X, Britt EC, Shows HW, Hjelmaas AJ, Shetty SK, Cushing EM, Li W, Dou A, ZHANG R, Davies BSJ. ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Mol Metab. 2017; 6:1137-1149.

  • ZHANG R. The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biology, 2016;6:150272.

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.

  • Fu Z, Abou-Samra AB, ZHANG R. An explanation for recent discrepancies in levels of human circulating betatrophin. Diabetologia. 2014;57:2232-4.

  • ZHANG R, Abou-Samra AB. Emerging roles of Lipasin as a critical lipid regulator. Biochem Biophys Res Commun. 2013;432:401-5.

  • ZHANG R. MNADK, a novel liver-enriched mitochondrion-localized NAD kinase. Biol Open. 2013;2:432-8.

  • Fu Z, Yao F, Abou-Samra AB, ZHANG R. Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem Biophys Res Commun. 2013;430:1126-31.

  • ZHANG R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424:786-92.

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.