Findings on sphingolipid biosynthesis may lead to new treatments for metabolic diseases
Brooklyn, NY – Almost all cell types exhibit some sort of polarity, which enables them to carry out specialized functions. Adherens junctions, which consist of the transmembrane protein cadherin and the intracellular components beta-catenin, alpha-catenin, and actin filaments, initiate cell-cell contacts and maintenance of cell polarity. Because all cell membranes that define cell boundaries and polarity contain lipid bi-layer structures, the lipid, including sphingolipid, environment could influence polarity, yet the mechanism underlying this remission is unknown.
Now, research led by SUNY Downstate Medical Center shows that blockage of sphingolipid de novo synthesis pathway (through knockout Serine Palmitoyltransferase, the key enzyme in the pathway) impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy, and promotes tumorigenesis. Importantly, the deficiency significantly reduces sphingomyelin but not other sphingolipids in hepatocyte plasma membrane, and greatly reduces cadherin, the major protein in adherens junctions, on the membrane. The deficiency affects cellular distribution of b-catenin, the central component of the canonical Wnt pathway.
Furthermore, such a defect can be partially corrected by sphingomyelin supplementation in vivo and in vitro. SUNY Downstate's Professor of Cell Biology Xian-Cheng Jiang, PhD, and Assistant Professor of Surgery Chongmin Huan, MD, PhD, are co-corresponding authors of the article detailing the research.
Dr. Jiang explained, "This was a seven-year effort and a breakthrough linking sphingolipid-mediated cell junctions and tumorigenesis. Our results, for the first time, show that plasma membrane sphingomyelin-related b-catenin cellular distribution is one the key factors in regulating hepatocyte polarity and tumorigenesis."
Dr. Jiang concludes, "This study also will provide a guide for the development of serine palmitoyltransferase inhibitors, which have a potential for the treatment of metabolic diseases such as diabetes."
The report, "Liver Serine Palmitoyltransferase (SPT) Activity Deficiency in Early Life Impairs Adherens Junctions and Promotes Tumorigenesis," published by Hepatology, is available online at: http://www.ncbi.nlm.nih.gov/pubmed/27642075 .
The article citation is: Li Z, Kabir I, Jiang H, Zhou H, Libien J, Zeng J, Stanek A, Ou P, Li KR, Zhang S, Bui HH, Kuo MS, Park TS, Kim B, Worgall TS, Huan C, Jiang XC. Liver Serine Palmitoyltransferase (SPT) Activity Deficiency in Early Life Impairs Adherens Junctions and Promotes Tumorigenesis. Hepatology. 2016 Sep 19. doi: 10.1002/hep.28845.
The research leading to the results published by Hepatology was supported by the National Institutes of Health, Award Number R56HL121409 and VA Merit Award Number 000900-01, as well as the Office of the Dean of the College of Medicine at SUNY Downstate. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
SUNY Downstate Medical Center, founded in 1860, was the first medical school in the United States to bring teaching out of the lecture hall and to the patient's bedside. A center of innovation and excellence in research and clinical service delivery, SUNY Downstate Medical Center comprises a College of Medicine, College of Nursing, College of Health Related Professions, School of Graduate Studies, School of Public Health, University Hospital of Brooklyn, and a multifaceted biotechnology initiative including the Downstate Biotechnology Incubator and BioBAT for early-stage and more mature companies, respectively.
SUNY Downstate ranks twelfth nationally in the number of alumni who are on the faculty of American medical schools. More physicians practicing in New York City have graduated from SUNY Downstate than from any other medical school. For more information, visit http://www.downstate.edu.