Dr. Yin-xiong Li

Department:
Medicine

Division:
Gastroenterology

Physical Address:
Box 3256
DUMC
Durham, NC 27710

Appointment Telephone:
9196682310

Research Interests:
My Laboratory is interested in the molecular mechanism of organogenesis of heart and liver development and related disease. We are focusing on two ongoing projects.

I. Exploring the molecular parthenogenesis of Fetal Alcohol Spectrum Defects (FASD). FASD is enormously detrimental to afflicted individuals, their families, and society as a whole. Although there has been great progress in delineating the mechanisms contributing to alcohol-induced birth defects, gaps in our knowledge still remain.

Our observations prompted a hypothesis that alcohol-inhibition of Shh ligand lipid-modifications decreases Shh ligand transport and secretion, disrupts the formation of a Shh gradient in the developmental field, and consequently contributes to FASD pathogenesis. Using in a zebrafish model, we recently demonstrated that alcohol exposure inhibits Hedgehog signaling and therefore leads to defects indicative of/resembling FASD in cellular differentiation and organogenesis. Transient loss of Hh signal transduction during specific developmental stages leads to permanent morphological abnormalities. At the molecular level, we have found that Shh interacts with Caveolin-1 to form protein complexes and are transported to the plasma membrane in lipid raft microdomains. Alcohol disrupts Shh-cholesterol modification resulting in a Shh trafficking defect and a Hh signal transduction defect. We are continuing this project on following three sections:

a. To determine whether Shh signaling inhibition is the primary defect for alcohol-induced development abnormalities;
b. To delineate the defective point(s) on the Hh signaling pathway that is(are) responsible for alcohol induced Shh signaling inhibition;
c. To determine whether alcohol disrupts lipid raft-mediated Shh ligand transportation and secretion.

The results obtained from this investigation will provide insights into a novel mechanism that may be responsible for alcohol’s teratogenic effects. The study may lead to new directionsfor the prevention and diagnosis of Fetal Alcohol Spectrum Defects.

II. Characterizing Adult Liver Stem Cells. Chronic liver disease is a leading cause of mortality and morbidity in the United States.  One of the primary treatments for liver failure is transplantation.  However, the current supply of donor livers is insufficient to match the need. Alternative strategies that employ adult hepatic stem cells as therapeutic agents or targets may provide future therapeutic means; however, our current understanding of hepatic stem cell biology is limited.

Sonic Hedgehog (Shh) signaling plays a pivotal role in embryonic patterning, tumorgenesis and adult tissue homeostasis.  We have isolated a small population of Ptc positive cells from adult zebrafish liver. These small sized Ptc positive nonparenchymal cells can differentiate into hepatocytes and cholangiocytes in vitro, and in vivo when transplanted into adult zebrafish with Tunicamycin induced liver injury. We have also found that disturbing cholesterol homeostasis can inhibit Hedgehog signaling by impairing cholesterol-modification of Shh.

Using zebrafish as the model, we aim to identify and isolate somatic liver stem cells, characterize Hedgehog signaling function on hepatic stem cell development, and determinate how disrupting cholesterol homeostasis may impair hedgehog signaling and hepatic stem cells function. Delineating the basic mechanisms that modulate the fate of liver stem cells in adults and characterizing the effects of cholesterol-lowing agents in this process has broad implications. It may identify other vulnerable factors responsible for insufficient regenerative ability during chronic liver injuries. It may also expand therapies of chronic liver disease such as alcoholic liver damages.

Publications:
2007 -- Pubmed # 17237799 -- Li YX*, Yang HT, Zdanowicz M, Sicklick JK, Qi Y, Camp TJ, Diehl AM. Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling.  Lab Invest.  2007  Mar;87(3):231-40.(* correspondence authors)

2007 -- Pubmed # 17476695 -- Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007 Jun;45(6):1366-74.

2006 -- Pubmed # 16339184 -- Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, Vivekanandan P, Ludlow JW, Owzar K, Chen W, Torbenson MS, Diehl AM. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006 Apr;27(4):748-57.

2005 -- Pubmed # 16170335 -- Sicklick JK, Li YX, Choi SS, Qi Y, Chen W, Bustamante M, Huang J, Zdanowicz M, Camp T, Torbenson MS, Rojkind M, Diehl AM. Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest. 2005 Nov;85(11):1368-80.

2004 -- Pubmed # 15618520 -- Wilbanks AM, Fralish GB, Kirby ML, Barak LS, Li YX*, Caron MG*. Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.  Science.  2004 Dec 24;306(5705):2264-7.(*co-correspondence authors).