Draft:Yu-Jui Yvonne Wan

Yu-Jui Yvonne Wan

Education
Dr. Wan was raised in Taipei. She attended the grade school named the National Taipei University of Education Experimental Elementary School and was awarded as an Outstanding Alumnus of that School. She continued her studies in the Taipei Municipal Zhong Shan Girls High School. She then received her Bachelor of Science with honors from Taipei Medical University, School of Pharmacy in 1979. Dr. Wan was elected as the Outstanding Alumnus of TMU due to her academic achievements.. . After graduating from TMU, she continued to advance her education at Hahnemann University, now known as Drexel University in Philadelphia, Pennsylvania in Experimental Pathology. She received a Master of Science degree in two years and a Doctor of Philosophy degree from the same institution two years later. She received experimental pathology training with a focus on development, cancer, and the liver from world-renowned pathologists including Dr. Ivan Damjanov and Dr. Emanuel Rubin.

Career
Dr. Wan began her research training as a post-doctoral fellow in the Laboratory of Developmental and Molecular Immunity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, Maryland. She continued at NICHD in the Human Genetics Branch working on liver differentiation and maturation using molecular biology approaches. Dr. Wan started her independent scientific career in 1989 as a faculty member in the Department of Pathology at the University of California, Los Angeles (UCLA). She established her laboratory at Harbor UCLA, where she studied the roles of retinoic acid and nuclear receptors in liver health and disease development, funded by the NIH. She also performed clinical research for longer than a decade to understand the drinking issues related to gene polymorphisms in ethnic minority populations funded by the NIH. She rose from assistant to associate and then full professor at UCLA before relocating to University of Kansas Medical Center.

In 2003, Dr. Wan served as a Full Professor for the Department of Pharmacology, Toxicology and Therapeutics at the University of Kansas Medical Center in Kansas City, Kansas. She was also heavily involved in other roles as the Leader of the Cancer Biology Program and the Founding Director of the Liver Center. She aided in obtaining multi-million-dollar NIH Centers of Biomedical Research Excellence (COBRE) funding, which benefited many liver researchers in the Midwest, enabling junior faculty to start their research laboratories and programs.

In 2012, Dr. Wan relocated to the University of California, Davis in Sacramento, California, with her appointment as Professor and Vice Chair of Research in the Department of Pathology and Laboratory Medicine. She became the 129th woman professor recruited to UC Davis. Her current research focus is the diet-gut-liver axis, which affects the development of metabolic dysfunction-associated steatohepatitis (MASH) and Hepatocellular carcinoma (HCC). She also studies the dietary effects via the gut microbiome influencing neuroplasticity and skin health, i.e., the diet-gut-brain or skin axis.

Dr. Wan also dedicates effort to collaborative research with many others. As the Vice Chair of Research for the Department of Pathology and Laboratory Medicine, she has contributed to increasing the department's research ranking at the national level by 25 positions since her induction as Vice Chair in 2012.

In 2022, Dr. Wan was advanced to the University of California Distinguished Professor, the highest campus-level faculty title that can be bestowed.

Awards and Honors
Dr. Wan has received many awards and honors for her dedication to science. A few examples are listed here. In 2003, she was recognized as a Distinguished Women in Research for years of dedicated service to advancing medical research, presented by California Congresswoman Jane Harman. Between 2007 and 2010, she received the Joy McCann Professorship in recognition of contributions to biomedical research and mentoring programs. In 2009, she was recognized as the Women in Toxicology SIG Elsevier Mentoring Award from the Society of Toxicology for outstanding mentorship. In 2010, she received the Chancellor’s Club Research Award at the University of Kansas. In 2019, Dr. Wan was awarded the Best Tea Health Advocate at the World Tea Expo for her lab’s innovative work uncovering the beneficial effects of epigallocatechin-3-gallate present in tea. In 2020, Dr. Wan was honored with the Dean’s Award of Excellence from the University of California, Davis for liver treatment and prevention.

Innovative Publications
Dr. Wan has published over 224 peer-reviewed scientific publications (http://www.ncbi.nlm.nih.gov/sites/myncbi/yu-jui.wan.1/bibliography/43144287/public/?sort=date&direction=ascending).

Below are the highlights:
Retinoic acid is the biologically active metabolite of vitamin A. Her earlier work examined the morphogenic roles of retinoic acid during development. She additionally uncovered novel mechanisms by which retinoic acid regulates hepatic phenotypes. Furthermore, she has characterized the metabolic roles of retinoic acid via nuclear receptors such as retinoic acid receptor (RAR) and retinoid X receptor (RXR). Some of these findings are summarized in a review paper titled “Retinoid Pathway and Cancer Therapeutics”.

Dr. Wan’s early works laid the foundation for her current drug discovery program, i.e., the production of novel “bacteria metabolite mimicries.” Nanodrugs, which are "retinoic acid-based histone deacetylase inhibitors," are used to address the shortage of specific microbial metabolites when patients have metabolic liver or colon disease, including cancer. Sponsored by the University of California, Davis, Dr. Wan has three US patent applications filed highlighting innovative findings. One of the invented nanodrugs has been funded by the NCI PREVENT Program to further study its colon cancer preventive effects with the aim for future clinical trials.

Her paper titled, “Hepatocyte-specific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver”. Retinoid x receptor (RXR) is the center of the nuclear receptor family because it is essential for many other nuclear receptors to function. Using the tissue-specific knockout mouse models, established in 2000, her lab reported the significance of hepatic RXRα on xenobiotic detoxification and endobiotic metabolism. Her lab uncovered the critical role of retinoic acid and its receptor in metabolism of lipids, carbohydrates, xenobiotics, and amino acids, as well as alcohol and xenobiotic detoxification. Those comprehensive studies established that retinoic acid is not just a differentiation agent; it has many metabolic functions.

The liver has a unique regeneration capability. The liver-to-body weight ratio is fixed to accommodate the metabolic load based on the body weight. There are many factors contributing to liver regeneration. In most cases, compensatory mechanisms allow the liver to complete regeneration and restore its original mass if one signal is being compromised. There are not many factors that are essential for liver regeneration. However, Dr. Wan’s lab uncovered that the pregnane X receptor (PXR) is essential for liver regeneration detailed, in a publication titled, “Pregnane X receptor is essential for normal progression of liver regeneration”. PXR, which forms a dimer with RXRα, controls xenobiotic and endobiotic metabolism and detoxification. In response to partial hepatectomy, lack of PXR inhibits hepatocyte proliferation, and the liver is not able to restore itself to its original mass at the anticipated end point of liver regeneration. These findings provide strong evidence that metabolism and detoxification are essential for hepatocyte proliferation and liver regeneration.

Bile acids are produced by hepatic and intestinal microbial enzymes. Various types of bile acids, via their receptors, regulate lipid and carbohydrate metabolism and host immunity. The data generated from the Wan lab established that bile acids are the intrinsic links that explain how the gut microbiome influences hepatic metabolic phenotype and disease development. Her lab was also one of the first to examined the impact of the gut microbiome on liver regeneration. The generated findings emphasized the significance of commensal microbes in tissue repair.

Many liver diseases including MASH and HCC, are male-predominant. Gender difference in disease development is frequently explained by differences in sex hormones. The Wan lab uncovered sexual dimorphism in the gut microbiome. These novel findings suggest that gut microbes and their metabolites might directly impact on gender differences in metabolic liver disease. In addition, the Wan lab was also the first to differentiate simple steatosis vs. cancer-prone steatosis based on gut microbes. Thus, using animal models, her works have uncovered that commensal microbes can predict liver cancer development early stage when the liver histology is the same between the cancer-prone vs. non-cancer prone groups.

In a manuscript titled “Western diet-induced dysbiosis in farnesoid x receptor knockout mice causes persistent hepatic inflammation after antibiotic treatment,” the detrimental effects of a Western diet by influencing the gut microbes to affect MASH development has been elucidated. MASH induced by bile acid receptor FXR deactivation can be prevented by antibiotic treatment, revealing the significance of the gut microbes in contributing to liver metabolic disease development. Additionally, Western diet intake led to persistent hepatic inflammation even after antibiotic treatment, suggesting that antibiotic-resistant bacteria were generated due to Western diet intake.

Dr. Wan’s research program not only focuses on the gut-liver axis, but also studies the effects of diet at the systemic levels covering the skin, brain, liver, and adipose tissues. She has compared different diets, simulating people’s preference in consuming carbohydrate/fat-enriched Western or a fat-enriched comfort diet. The data revealed that a Western diet is highly inflammatory and profibrotic compared to a high-fat diet that is efficient in body weight gain. Moreover, the inflammatory effect of a Western diet is reversible by dietary switching and reducing bile acid pool size. Those findings establish the significance of the diet-gut-organ axis. Moreover, body weight itself does not address all metabolic-related health issues.

The anti-cancer effects of epigallocatechin-3-gallate (EGCG) found in green tea have been known for many years. The health benefit of EGCG has been explained simply by its antioxidant effect. The Wan lab was the first to demonstrate that EGCG shapes the gut microbiome by specifically enriching Akkermansia muciniphila thereby improving insulin sensitivity and metabolism. Moreover, Dr. Wan strongly advocate using precision dietary supplementation to improve or treat diseases. Information can be found in a manuscript titled “Precision dietary supplementation based on personal gut microbiota”.

There are currently many health issues that have no effective treatment options. Based on the shortage of bacteria found in MASH mice, the Wan lab used probiotics B. infantis, A. muciniphila, and VSL#3 as well as bacterial metabolites to prevent or treat MASH or metabolic health issues. It demonstrated promising outcomes in animal models. VSL#3 is an FDA-approved probiotic medication used to treat colitis. For the first time, the Wan lab showed that it can also treat MASH, revealing translational potential. The underlying mechanisms are partly due to the increase in bacterial enzyme bile salt hydrolase, which converts conjugated bile acids into free bile acid to improve metabolism and immunity.

Hyperemesis gravidarum is a serious gastrointestinal health issue during pregnancy that does not have an effective treatment option. Dr. Wan and Dr. Albert Liu at UC Davis, Department of Obstetrics and Gynecology, led the clinical trials and provided evidence that probiotics reduces hyperemesis gravidarum and improve life quality during pregnancy. The studied probiotics are readily available over the counter and have an immediate health benefit for pregnant women.

2023-2024, Wan's research programs uncovered predictors and novel liquid biomarkers for cancer risks by employing bioinformatics and machine-learning approaches. Her lab also uncovered novel options to treat mouse liver cancer, i.e., hepatocellular carcinoma

Journal Cover Stories and News Features
A publication entitled “BCG as an innovative option for HCC treatment: Repurposing and Mechanistic Insights” was included in:

UC Davis Health News, February 20, 2024, https://health.ucdavis.edu/news/headlines/tb-vaccine-shrinks-liver-cancer-tumors-in-mice/2024/02\.

The Cancer Letter, Vol 50, No 11, March 8, 2024, https://cancerletter.com/clinical-roundup/20240308_8d/

Advanced Science- 10th-anniversary special collection. https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)2198-3844.10thAnniversary

Wan lab’s work on BCG was filmed by Voice of America: https://www.golosameriki.com/a/lechenie-raka-vaktsinoj-btszh-i-novyj-yazyk-detali/7530392.htm l.

A publication entitled “Targeting stroma and tumor, silencing galectin-1 treats orthotopic mouse HCC” was featured in UC Davis Health News. https://health.ucdavis.edu/news/headlines/scientists-find-gene-therapy-reduces-liver-cancer-in-animal-model/2023/11

A publication entitled "miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism" was featured in:

The Cancer Letter, Vol 49, No 24, September 15, 2023. https://cancerletter.com/clinical-roundup/20230915_9q/

UC Davis Health News, August 2023. https://health.ucdavis.edu/news/headlines/gene-therapy-study-identifies-potential-new-treatment-for-liver-cancer/2023/08

Newswise, https://www.newswise.com/articles/gene-therapy-study-identifies-potential-new-treatment-for-liver-cancer.

Eureka alert, https://www.eEurekalert.org/news-releases/999460.

A publication entitled “Probiotics improve gastrointestinal function and life quality in pregnancy” was in news announcement: https://health.ucdavis.edu/health-news/contenthub/probiotics-improve-nausea-and-vomiting-in-pregnancy-according-to-new-study/2021/12

A publication entitled “Gender Differences in Bile Acids and Microbiota in Relationship with Gender Dissimilarity in Steatosis Induced by Diet and FXR Inactivation” was selected as a feature article in Nutrition Frontiers, a publication of the Nutritional Science Research Group (NSRG), NCI. Summer 2017: https://prevention.cancer.gov/news-and-events/news/nutrition-frontiers-summer-0

A publication entitled “Western Diet–Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment” was selected for the Cover story of American Journal of Pathology: https://www.elsevier.com/about/press-releases/research-and-journals/chronic-liver-inflammation-linked-to-western-diet and was subsequently featured in news release about the cover story: https://www.eurekalert.org/pub_releases/2017-07/e-cli071017.php

A publication entitled “Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration” was selected to be the highlight of the March issue of the Journal of Hepatology in 2016. https://www.journal-of-hepatology.eu/article/S0168-8278(15)00670-4/fulltext

Dr. Wan was selected to be in a featured story in the Synthesis, UCDMC Cancer Center: https://health.ucdavis.edu/synthesis/issues/spring2015/gutreaction.html

A publication entitled “Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis” was selected for a news release: https://www.eurekalert.org/news-releases/461515

A published article entitled “Bacteria Tightrope”, was written after Dr. Wan was selected to be interviewed by Nature: http://www.nature.com/nature/journal/v516/n7529_supp/full/516S14a.html

A publication entitled “Alteration of nuclear receptor-mediated signaling pathways in HCV patients with and without a history of alcohol drinking” was selected to be the cover story of the December issue of Hepatology in 2011. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.24645

A publication entitled “Enrichment of Nur77 mediated by RARβ leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and HDACi” was selected to be the cover story of the March issue of Hepatology in 2011. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.24101

A publication entitled “The Interaction of reward genes with environmental factors in contribution to alcoholism in Mexican Americans” was selected to be a journal highlight and included in the news release: http://www.eurekalert.org/pub_releases/2009-09/ace-ear091109.php. Additionally, the publication was selected to be the featured article in MDLinx.com: http://www.mdlinx.com/internalmdlinx/news-article.cfm/2887596

Recorded Lectures:

 * https://video.ucdavis.edu/media/GTI+-+Yvonne+Wan+01-24-2019/1_1vxadre5
 * https://ucdhs.hosted.panopto.com/Panopto/Pages/Viewer.aspx?id=50f00e6d-6d28-4766-89a3-ab1a01280a10
 * https://www.vumedi.com/video/th-gut-microbiota-hepatic-inflamation-and-carcinogenesis/