Professor A Xu

Professor

Department of Pharmacology & Pharmacy, The University of Hong Kong

About me

Professor Aimin XuProfessor

Professor Aimin Xu (徐愛民)
BMed Anhui, MSc, PhD Auck

Director, State Key Laboratory of Pharmaceutical Biotechnology, HKU (www.sklpb.hku.hk)

Director, Antibody and Immunoassay Services, HKU
(www.antibody.hku.hk)

Memberships:
Deputy Chair, Biochemical Journal
American Diabetes Association
American society of Biochemistry and Molecular Biology HBHA center, HKU

Editorships:
Editor: Clinical Science, PLOS One
Editorial Board member, Journal of Obesity, Journal of Diabetes, Adipocytes, Cardiovascular Drugs and Therapy Editor

My research interests

Obesity is a major risk factor of type 2 diabetes (T2DM), insulin resistance and cardiovascular diseases (CVDs). In obesity, chronic metabolic stresses trigger adipose tissue inflammation and promote macrophage infiltration, resulting in aberrant secretion of bioactive peptides (known as adipokines). Our primary research interest is to investigate the role of adipokines in the pathogenesis of obesity-related insulin resistance, systemic inflammation, T2DM and vascular dysfunctions in animal models and human subjects. Our long-term goal is to develop adipokine-based diagnostic and therapeutic strategies for obesity-related cardio-metabolic complications.

Professor Xu and his research associates (click image to enlarge)     

  • Identification and functional characterization of adipokine netowork:
    Using an integrated proteomics-based approach, we have identified multiple posttranslationally modified isoforms of adiponectin, and have demonstrated that hydroxylation and subsequent glycosylation of several lysine residues at the collagenous domain are obligatory for insulin-sensitizing effects of adiponectin by promoting the formation of high molecular weight oligomeric complexes (Wang Y, JBC, 2002, 2005, 2006; Biohcem. J, 2008; Xu A, JCI, 2003). We have also identified the circulating form of adipocyte fatty acid-binding protein (A-FABP) and lipocalin-2 as pro-inflammatory adipokines mediating toxic lipids-induced insulin resistance and vascular dysfunction (Xu A, Clin Chem: 2006; Circulation: 2007; Hui X, JBC:2010). More recently, we have demonstrated that fibroblast growth factor (FGF21), an anti-diabetic hormone traditionally thought to be produced from hepatocytes, is also secreted from adipose tissues (Zhang X, Diabetes, 2008 and Lin Z, Cell Metabolism, 2013). Furthermore, we found that adipose-derived FGF21 exerts its anti-diabetic activities by inducing adiponectin production (Fig 1). Currently, we are investigating the mechanisms by which FGF21 controls adiponectin production under physiological and pathological conditions.
  • Signaling mechanisms underlying the insulin-sensitizing and vascular protective effects of adiponectin:
    Adiponectin is one of the few adipokines with insulin-sensitizing and cardiovascular protective properties, but its mechanisms of actions remain poorly characterized. In 2007, We identified APPL1, an intracellular adaptor protein, as a key signaling molecule that bind to adiponectin receptors mediating adiponectin-induced activation of AMP-activated protein kinase (AMPK), thereby inducing eNOS activation and NO production in endothelial cells (Cheng KK, Diabetes, 2007). Our subsequent studies demonstrated that APPL1 is also a key component of insulin-evoked signaling cascade, by promoting membrane targeting and translocation of the protein kinase Akt (Cheng KK, Cell Metab. 2009; BJ, 2013). Furthermore, using APPL1 transgenic and knockout mice, we have found that APPL1 plays a central role in controlling vascular homeostasis as well as insulin secretion (Cheng KK, PNAS, 2012; Wang Y, Diabetes, 2011).

    We have also uncovered an important role of adiponectin in preventing diabetes-induced vascular injury, by promoting the functions of endothelial progenitor cells (EPCs) via an AMPK-dependent mechanism (Chang J, Diabetes, 2010). In light of the key role of AMPK in mediating the endothelium-protective effects of adiponectin, we have generated transgenic mice with endothelium-selective constitutive AMPK activation, and found that endothelium-selective activation of AMPK is sufficient to prevent diabetes-associated impairment of vascular repair via induction of heme oxygenase-1 (HO1) pathway, which in turn augments EPCs-mediated endothelial regeneration (Li Y, Circulation, 2012) (Fig 2). We are currently investigating the roles of FGF21/adiponectin axis in protecting obesity-induced vascular inflammation and atherosclerosis in both rodents and large animals.
  • Translational research: Adipokines-based assay development, clinical diagnosis and drug discovery:
    Through the Antibody and Immunoassay Service (AIS, www.antibody.hku.hk), we have developed over 20 highly specific immunoassay kits for new adipokines and other biomarkers related to cardio-metabolic diseases. These assay kits are now being commercialized for basic and clinical research, clinical diagnosis and high throughput drug screening. We are working with several overseas and Mainland hospitals to conduct long-term prospective studies to validate the clinical values of our several adipokine assays for risk prediction and early diagnosis of cardiovascular complications of diabetes in different ethnic groups. In addition, we are now using these adipokines as biomarkers for high throughput screening of new compounds from medicinal herbs with anti-diabetic and vasculoprotective properties and for discovery of drug candidates for obesity-related medical complications by targeting the adipo-vascular axis.
Professor A Xu Professor A Xu
(click image to enlarge)
Selected Publications

Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A*, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metabolism. 2013, 17:779-89 (cited ~30 times within 8 months after publication)

Cheng KK, Lam KS, Wu D, Wang Y.. and Xu A*. APPL1 potentiates insulin secretion in pancreatic beta-cells by increasing Akt-dependent expression of SNARE proteins in mice. Proc. Natl. Acad. Sci. USA. 2012, 109:8919-24, selected for commentary.

Li FY, Lam KS, Tse HF, Chen C, Wang Y, Vanhoutte PM, Xu A*. Endothelium-selective activation of AMP-activated protein kinase prevents diabetes mellitus-induced impairment in vascular function and reendothelialization via induction of heme oxygenase-1 in mice. Circulation. 2012, 126:1267-77.

Ye D, Li Y, Lam KS, Li H, Jia W, Wang Y, Man K, Li X and Xu A*. TLR4 mediates obesity-induced nonalcoholic steatohepatitis through activation of X-box binding protein in mice. Gut. 2012, 61: 1058-67

Wang Y, Cheng KK, Lam KS, Wu D, Wang Y, Huang Y, Vanhoutte PM, Sweeney G, Li Y, Xu A*. APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice. Diabetes, 2011, 60: 3044-54.

Wong WT, Tian XY, Xu A*, Yu J, Lau CW, Hoo R, Wang Y, Lee VW, Lam KS, Vanhoutte PM, and Huang Y. The obligatory role of adiponectin in restoring endothelial function in PPARγ agonist-treated diabetic mice. Cell Metabolism, 2011, 16:101-15.

Chang J , Li Y , Huang Y , Lam KS, Hoo LC, Wong WT, Cheng KK, Wang Y, Vanhoutte PM , and Xu A*. Adiponectin Prevents Diabetic Premature Senescence of Endothelial Progenitor Cells and Promotes Endothelial Repair by Suppressing the p38 MAP kinase/p16INK4A Signaling Pathway. Diabetes, 2010, 59: 2949-59

Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney, Zhu W, Vanhoutte PM, Kraegen EW and Xu A*. APPL1 Potentiates Insulin-mediated Inhibition of Hepatic Glucose Production and Alleviates Diabetes via Akt Activation in Mice. Cell Metabolism, 2009, 9:417-27.

Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A*. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes, 2008, 57:1246-53.

Cheng KK, Lam KS, Wang Y, Huang Y, Carling D, Wu D, Wong C, Xu A*. Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes. 2007, 56:1387-94 (cited over 170 times).

Xu A*, Lam MCL, Chan KW, Wang Y, Hoo RCL, Zhang JL, Tso A and Lam KSL, ANGPTL4 decreases blood glucose, improve glucose tolerance, but induces hyperlipidemia and hepatic steatosis in mice, Proc. Natl. Acad. Sci. USA, 2005, 102, 6089-6091

Xu A*, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 2003, 112:91-100. (selected for the cover story of this issue, CITED OVER 980 times).

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HKU
Contact Information

Professor A Xu

Office:
8/F, 21 Sassoon Road, Li Ka Shing Faculty of Medicine, Laboratory Block, Faculty of Medicine Building, Hong Kong SAR, China.

Email amxu@hku.hk

HKU Hub HKU Hub

Collaborations

Dr. Gary Sweeney, York University, Canada.

Prof. Edward Kraegen, Garvin's institute, Australia.

Prof. Jia Weiping, Shanghai Diabetes Center, China

Funding source

2012 -


Theme-based Research Scheme (T12-705/11) - Co-I

- Personalized medicine for cardiovascular diseases


General Research Fund (784111M) -PI

- The Liver-derived Hormone FGF21 as a Novel Regulator of Vascular Function: Molecular Basis and Physiological Implications


 

2011 -


RGC collaborative research fund (HKU4/CRF/10) -PI

- A multiple disciplinary approach to investigate vascular dysfunction in obesity and diabetes: From molecular mechanism to therapeutic intervention


National "973" basic research on diabetes matching fund (2011CB504004) -PI

- 2型糖尿病发生发展的分子机制研究 (Molecular basis of type 2 diabetes).


General Research Fund (783010M) -PI

- APPL2 as a Negative Regulator of Insulin Sensitivity and Glucose Uptake in Skeletal Muscle: A Novel Pathway Leading to Insulin Resistance?


 

2010 -


RGC collaborative Research Fund (HKU 3/CRF/09) - Co-I

- To Establish a Metabolic Study Center in Hong Kong: Focusing on the liver-derived hormones


General Research fund (781309M) -PI

- Characterization of Novel Adaptor Proteins Involved in Regulating Insulin Sensitivity and Glucose Homeostasis: from Molecular Mechanism to Physiological Implication



2009-


NSFC/RGC joint research scheme 2008 (NHKU 735_08) -PI

- Adipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications


General Research Fund 2008 (779608M) -PI

- Protective roles of AMP-activated protein kinase against vascular disease in diabetes: Molecular mechanisms and therapeutic intervention

Useful link

Antibody and Immunoassay Services

- www.antibody.hku.hk