Center for Translational Biomedical Research

Zhou Research Group

Research Focus

Metabolic liver diseases

Zhanxiang Zhou, Ph.D.,
CTBR Co-Director, Professor, Nutrition
Tel: 704-250-5800
Email: z_zhou@uncg.edu

RESEARCH OVERVIEW

Dr. Zhangxiang Zhou’s laboratory examines how imbalanced dietary consumption, such as the abuse of alcohol and other hallmarks of contemporary Western life, contributes to the development of liver diseases. 1 in 10 Americans have some form of liver disease, and the number of deaths related to these diseases may be higher than we think. (Mayo Clinic researchers recently challenged CDC statistics and placed liver disease as the 8th leading cause of American deaths). With funding from the National Institutes of Health, the Zhou Research Group currently focuses on combating fatty liver disease, in which excess lipids deposit in the liver due to alcohol abuse or obesity. Unchecked fatty liver disease can progress to hepatitis (inflammation), liver cirrhosis (scarring), and liver failure. CTBR researchers in the Zhou group are exploring the biological causes and progression of fatty liver disease, methods for early diagnosis, and particular dietary and pharmaceutical interventions that could prevent and even reverse damages caused by the disease.

CURRENT PROJECT-ALDEHYDE TOXICITY

Investigating the mechanisms by which aldehydes impair cell function and induce organ damage, and developing strategies to speed up aldehyde clearance. Alcohol consumption exerts toxic effects on the body with gut, liver and brain as the major target organs. Aldehyde generation is a feature of alcohol intoxication. While alcohol metabolism generates acetaldehyde, lipid peroxidation produces lipid aldehydes such as 4-hydroxynonenal and malondialdehyde. Accumulation of aldehydes has been detected in intestinal contents, liver, blood and brain after alcohol intoxication. This project aims to investigate the molecular mechanisms by which aldehydes mediate alcohol-induced cytotoxicity at the gut-liver-brain axis.

CURRENT PROJECT-LIPOTOXICITY

Lipid accumulation is one of the most fundamental cellular disorders in the development of alcoholic liver disease. During the past decades, great efforts have been paid to understand the mechanisms by which alcohol abuse induces hepatic accumulation of lipid droplets, particularly triglyceride. However, increasing evidence suggests that free fatty acids are more toxic than triglyceride. Therefore, it is important to understand the mechanism by which alcohol abuse increases the hepatic fatty acid level and by which fatty acids induce cell injury. This project aims to investigate the mechanisms by which alcohol abuse increases the hepatic fatty acid level and by which fatty acids induce cell injury. We are also interested in understanding of how dietary factors may modulate fatty acid homeostasis in the liver.

CURRENT PROJECT-ORGAN INTERACTIONS

Increasing evidence support a concept that extra-hepatic factors critically involve in the pathogenesis of liver diseases. The most well studied factors include endotoxin penetration from the intestine and excess fatty acid release from the white adipose tissue. Only trace amount of intestinal endotoxin can penetrate to the blood at normal condition. However, blood endotoxin level will be elevated, namely endotoxemia, at disease condition such as alcoholic and nonalcoholic liver disease. Endotoxin plays critical role in development of hepatitis by triggering production of proinflammatory cytokine. On the other hand, lipids stored in the white adipose tissue could be released and deposited in the liver at alcohol abuse or obesity conditions. The objectives of this project are to investigate the mechanisms by which extra-hepatic factor are generated and by which these factors contribute to the pathogenesis of liver damage

CURRENT PROJECT-DIETARY INTERVENTIONS

Exploring dietary interventions to prevent or treat liver diseases. Liver is the major organ responsible for metabolism in the body. The metabolic function of the liver can be disturbed at disease conditions such as alcohol exposure and toxicant exposure. Functional disorder of the liver may, in turn, affect nutrient absorption and metabolism, leading to nutritional deficiency. Previous reports from our research group have shown that alcohol abuse zinc deficiency and improvement of zinc homeostasis by dietary zinc supplementation ameliorates alcoholic liver disease. Other dietary factors such as niacin and saturated fat also have beneficial effects on alcoholic liver disease. The goal of this project is to screen nutrients and natural products which may protect against liver disease work via intrahepatic or extrahepatic mechanisms.

CURRENT MEMBERS

  • Dr. Wei Zhong, D.V.M., Ph.D., Research Scientist
  • Dr. Wenliang Zhang, Ph.D., Research Scientist
  • Dr. Liuyi Hao, Ph.D. Postdoctoral Fellow

PUBLICATIONS (2010-)

  1. Zhong W, Zhang W, Li Q, Xia G, Sun Q, Sun X, Tan X, Sun XG, Zhou Z. Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol (in press).
  2. Zhang W, Zhong W, Sun X, Sun Q, Tan X, Li Q, Sun XG, Zhou Z. Visceral white adipose tissue is susceptible to alcohol-induced lipodystrophy in rats: Role of acetaldehyde. Alcohol Clin Exp Res (in press).
  3. Zhong W, Zhou Z. Alterations of the gut microbiome and metabolome in alcoholic liver disease. World J Gastrointest Pathophysiol. 2014; 5:514-522.
  4. Koo I, Wei X, Shi X, Zhou Z, Kim S, Zhang X. Constructing Metabolic Association Networks Using High-dimensional Mass Spectrometry Data. Chemometr Intell Lab Syst. 2014; 138:193-202.
  5. Li Q, Xie G, Zhang W, Zhong W, Sun X, Tan X, Sun XG, Jia W, Zhou Z. Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 2014; 38:1982-1992.
  6. Sun Q, Li Q, Zhong W, Zhang J, Sun X, Tan X, Yin X, Sun X, Zhang X, Zhou Z. Dysregulation of hepatic zinc transporters in a mouse model of alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2014; 307:G313-322.
  7. Wang Z, Dou X, Li S, Zhang X, Sun X, Zhou Z, Song Z. Nrf2 activation-induced hepatic VLDLR overexpression in response to oxidative stress contributes to alcoholic liver disease in mice. Hepatology 2014; 59:1381-92.
  8. Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G, Li H, Cai S, Xie D, Huang C, Ge W, Zhou Z, Xu LX, Jia W, Zheng S, Yen Y, Jia W. A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res. 2014; 20:2136-2146.
  9. Shen W, Wolf PG, Carbonero F, Zhong W, Reid T, Gaskins HR, McIntosh MK. Intestinal and systemic inflammatory responses are positively associated with sulfidogenic bacteria abundance in high-fat-fed male C57BL/6J mice. J Nutr. 2014; 144:1181-1187.
  10. Xie G, Zhong W, Zheng X, LiQ, Qiu Y, Li H, Chen H, Zhou Z, Jia W. Chronic Ethanol Consumption Alters Mammalian Gastrointestinal Content Metabolites. J Proteomics Res 2013; 12:3297-3306.
  11. Sun X, Luo W, Tan X, Li Q, Zhao Y, Zhong W, Sun X, Brouwer C, Zhou Z. Increased plasma corticosterone contributes to the development of alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2013; 305:G849-861.
  12. Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Am J Physiol Gastrointest Liver Physiol 2013; 305:G919-932.
  13. Zhong W, Zhao Y, Sun X, Song Z, McClain CJ, Zhou Z. Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice: involvement of intrahepatic and extrahepatic factors. PLoS One 2013; 8:e76522.
  14. Song M, Schuschke DA, Zhou Z, Chen T, Shi X, Zhang J, Zhang X, Pierce WM Jr, Johnson WT, Vos MB, McClain CJ. Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats. Obesity (Silver Spring). 2013; 21:1669-75.
  15. Xie G, Zhong W, Li H, Li Q, Qiu Y, Zheng X, Chen H, Zhao X, Zhang S, Zhou Z, Zeisel SH, Jia W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. FASEB J. 2013; 27:3583-3593.
  16. Wang X, Bu HF, Zhong W, Asai A, Zhou Z, Tan X. MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage engulfing apoptotic cells. Mol Medicine 2013; 19:170-182.
  17. Tan B, Qiu Y, Zou X, Chen T, Xie G, Cheng Y, Dong T, Zhao L, Feng B, Hu X, Xu LX, Zhao A, Zhang M, Cai G, Cai S, Zhou Z, Zheng M, Zhang Y, Jia W. Metabonomics Identifies Serum Metabolite Markers of Colorectal Cancer. J Proteome Res. 2013; 12:3000-3009.
  18. Li Q, Zhong W, Qiu Y, Kang X, Zhao Y, Sun X, Tan X, Sun X, Jia W, Zhou Z. Preservation of hepatocyte nuclear factor 4α contributes to the beneficial effect of dietary medium chain triglyceride on alcohol-induced hepatic lipid dyshomeostasis in rats. Alcohol Clin Exp Res 2013; 37:587-598.
  19. Wei X, Shi X, Zhong W, Zhao Y, Tang Y, Sun W, Yin X, Bogdanov B, Kim S, McClain C, Zhou Z, Zhang X. Chronic Alcohol Exposure Disturbs Lipid Homeostasis at the Adipose Tissue-Liver Axis in mice: Analysis of Triacylglycerols Using High-Resolution Mass Spectrometry in Combination with in vivo Metabolite Deuterium Labeling. PLoS One 2013; 8:e55382.
  20. Tan X, Xie G, Sun X, Li Q, Zhong W, Qiao P, Sun X, Jia W, Zhou Z. High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways. PLoS One 2013; 8:e61409.
  21. Zheng X, Qiu Y, Zhong W, Baxster S, Su M, Li Q, Xie G, Ore BM, Diao S, Spencer MD, Seizel SH, Zhou Z, Zhao A, Jia W. A targeted metabolomic protocol for short-chain fatty acids and branched-chain amino acids. Metabolomics, 2013; 9:818-827.
  22. Li H, Zhou Y, Zhao A, Qiu Y, Xie G, Jiang Q, Zheng X, Zhong W, Sun X, Zhou Z, Jia W. Asymmetric dimethylarginine attenuates serum starvation-induced apoptosis via suppression of the Fas (APO-1/CD95)/JNK (SAPK) pathway. Cell Death Dis. 2013;4:e830.doi:10.1038/cddis.2013.345.
  23. Tan X, Sun X, Li Q, Zhao Y, Zhong W, Sun S, Jia W, McClain CJ, Zhou Z. Leptin administration reverses early stage of alcoholic liver disease in mice. Am J Pathol 2012; 181:1279-86.
  24. Sun X, Tang Y, Tan X, Li Q, Zhong W, Sun X, Jia W, McClain CJ, Zhou Z. Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone improves lipid homeostasis at the adipose tissue-liver axis in ethanol-fed mice. Am J Physiol Gastrointest Liver Physiol. 2012; 302:G548-557.
  25. Zhong W, Zhao Y, Tang Y, Wei X, Shi X, Sun W, Sun X, Yin X, Sun X, Kim S, McClain CJ, Zhang X, Zhou Z. Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: Role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis. Am J Pathol 2012; 180:998-1007.
  26. Zhong W, Zhou Z. Zinc in regulation of epithelial tight junction proteins in alcohol-induced intestinal barrier dysfunction. J Epithelial Biol Pharmacol 2012; 5(Suppl. 1-M3):19-27.
  27. Song M, Schuschke DA, Zhou Z, Chen T, Pierce WM, Wang R, Thomas Johnson W, McClain CJ. High Fructose Feeding Induces Copper Deficiency in Sprague-Dawley rats: A Novel Mechanism for Obesity Related Fatty Liver. J Hepatol. 2012; 56:433-40.
  28. Tan Y, Li X, Prabhu SD, Brittian KR, Chen Q, Yin X, McClain CJ, Zhou Z, Cai L. Angiotensin II plays a critical role in alcohol-induced cardiac nitrative damage, cell death, remodeling, and cardiomyopathy in a protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase-dependent manner. J Am Coll Cardiol. 2012; 59:1477-1486.
  29. Mohammad MK, Zhou Z, Cave M, Barve A, McClain CJ. Zinc and liver disease. Nutrition in Clinical Practice 2012; 27:8-20.
  30. Wei J, Xie G, Ge S, Qiu Y, Liu W, Lu A, Chen T, Li H, Zhou Z, Jia W. Metabolic transformation of DMBA-induced carcinogenesis and inhibitory effect of salvianolic acid b and breviscapine treatment. J Proteome Res. 2012; 11:1302-13016.
  31. Wang T, Sun X, Zhou Z, Chen G. Effects of microfluidization process on physicochemical properties of wheat bran. Food Res International 2012; 48:742-747.
  32. Zhao Y, Zhong W, Sun X, Song Z, Kang Y, McClain C, Zhou Z. Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism. Am J Pathol 2011; 179:693-702.
  33. Wang Z, Pini M, Yao T, Zhou Z, Sun C, Fantuzzi G, Song Z. Homocysteine suppresses lipolysis in adipocytes by activating the AMPK pathway. Am J Physiol Endocrinol Metab 2011; 301:E703-712.
  34. Song M, Zhou Z, Chen T, Zhang J, McClain CJ. Copper Deficiency Exacerbates Bile Duct Ligation-Induced Liver Injury and Fibrosis in Rats. J Pharmacol Exp Ther. 2011; 339:298-306.
  35. Zheng X, Xie G, Zhao A; Zhao L, Yao Chun; Chiu N, Zhou Z, Bao Y, Jia W, Nicholson J, Jia W. The Footprints of Gut Microbial-Mammalian Co-Metabolism. J Proteome Res. 2011; 10:5512-22.
  36. Hua Y, Qiu Y, Zhao A, Wang X, Chen T, Zhang Z, Chi Y, Li Q, Sun W, Li G, Cai Z, Zhou Z, Jia W. Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM-8 osteosarcoma cell transplantation. J Proteome Res. 2011; 10:3513-3521.
  37. Zhang J, Fang A, Wang B, Kim SH, Bogdanov B, Zhou Z, McClain C, Zhang X. iMatch: A retention index tool for analysis of gas chromatography-mass spectrometry data. J Chromatogr A. 2011; 1218:  6522– 6530.
  38. Zhao Y, Zhang J, Wang B, Kim SH, Fang A, Bogdanov B, Zhou Z, McClain C, Zhang X. A method of calculating the second dimension retention index in comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. J Chromatogr A. 2011; 1218:2577-2583.
  39. Wei X, Sun W, Shi X, Koo I, Wang B, Yin X, Tang Y, Bogdanov B, Kim SH, Zhou Z, McClain CJ, Zhang X. MetSign: A computational platform for high-resolution mass spectrometry-based metabolomics. Anal. Chem. 2011; 83:7668-7675.
  40. Zhou Z. Zinc and alcoholic liver disease. Dig Dis. 2010; 28:G745-750.
  41. Zhong W, McClain CJ, Cave M, Kang YJ, Zhou Z. The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am J Physiol. 2010; 298:G625-G633.
  42. Zhong W, Zhao Y, McClain CJ, Kang YJ, Zhou Z. Inactivation of hepatocyte nuclear factor-α mediates alcohol-induced down-regulation of intestinal tight junction proteins. Am J Physiol. 2010; 299:G643-G651.